<?xml version="1.0" encoding="utf-8"?>
<!--Generated by DFIN XBRL Instance Document - http://www.dfinsolutions.com/ - Version R3.0 - on 08-May-2025 [12:35:48] {AM}-->
<linkbase xmlns="http://www.xbrl.org/2003/linkbase" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xlink="http://www.w3.org/1999/xlink" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#ConsolidatedBalanceSheets" roleURI="http://www.scilexholding.com/role/ConsolidatedBalanceSheets" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#CondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" roleURI="http://www.scilexholding.com/role/CondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#CondensedConsolidatedStatementsOfCashFlows" roleURI="http://www.scilexholding.com/role/CondensedConsolidatedStatementsOfCashFlows" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#NatureOfOperationsAndBasisOfPresentationScheduleOfCashAndCashEquivalentsDetails" roleURI="http://www.scilexholding.com/role/NatureOfOperationsAndBasisOfPresentationScheduleOfCashAndCashEquivalentsDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#BalanceSheetComponentsScheduleOfPropertyAndEquipmentDetails" roleURI="http://www.scilexholding.com/role/BalanceSheetComponentsScheduleOfPropertyAndEquipmentDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#BalanceSheetComponentsScheduleOfAcrcuedExpensesDetailsDetails" roleURI="http://www.scilexholding.com/role/BalanceSheetComponentsScheduleOfAcrcuedExpensesDetailsDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#GoodwillAndIntangibleAssetsEstimatedFutureAmortizationExpenseOfIntangibleAssetsDetails" roleURI="http://www.scilexholding.com/role/GoodwillAndIntangibleAssetsEstimatedFutureAmortizationExpenseOfIntangibleAssetsDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#CommitmentsAndContingenciesScheduleOfLeaseMaturitiesOfLeaseLiabilitiesDetails" roleURI="http://www.scilexholding.com/role/CommitmentsAndContingenciesScheduleOfLeaseMaturitiesOfLeaseLiabilitiesDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#IncomeTaxesScheduleOfComponentsOfBenefitForIncomeTaxesDetails" roleURI="http://www.scilexholding.com/role/IncomeTaxesScheduleOfComponentsOfBenefitForIncomeTaxesDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#IncomeTaxesScheduleOfDeferredTaxLiabilitiesAndRelatedValuationAllowanceDetails" roleURI="http://www.scilexholding.com/role/IncomeTaxesScheduleOfDeferredTaxLiabilitiesAndRelatedValuationAllowanceDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#IncomeTaxesScheduleOfEffectiveIncomeTaxRateReconciliationDetails" roleURI="http://www.scilexholding.com/role/IncomeTaxesScheduleOfEffectiveIncomeTaxRateReconciliationDetails" />
<roleRef xlink:type="simple" xlink:href="sclx-20241231.xsd#CommitmentsAndContingenciesScheduleOfLeaseMaturitiesOfLeaseLiabilitiesDetailsAlternate1" roleURI="http://www.scilexholding.com/role/CommitmentsAndContingenciesScheduleOfLeaseMaturitiesOfLeaseLiabilitiesDetailsAlternate1" />
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/BalanceSheetComponentsScheduleOfAcrcuedExpensesDetailsDetails">
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_AccruedExpenses" xlink:label="loc_SCLX_AccruedExpenses" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccruedProfessionalFeesCurrent" xlink:label="loc_us-gaap_AccruedProfessionalFeesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_SCLX_AccruedExpenses" xlink:to="loc_us-gaap_AccruedProfessionalFeesCurrent" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccruedMarketingCostsCurrent" xlink:label="loc_us-gaap_AccruedMarketingCostsCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_SCLX_AccruedExpenses" xlink:to="loc_us-gaap_AccruedMarketingCostsCurrent" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_AccruedResearchAndDevelopmentCosts" xlink:label="loc_SCLX_AccruedResearchAndDevelopmentCosts" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_SCLX_AccruedExpenses" xlink:to="loc_SCLX_AccruedResearchAndDevelopmentCosts" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_TaxesPayableCurrentAndNoncurrent" xlink:label="loc_us-gaap_TaxesPayableCurrentAndNoncurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_SCLX_AccruedExpenses" xlink:to="loc_us-gaap_TaxesPayableCurrentAndNoncurrent" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccruedLiabilitiesFairValueDisclosure" xlink:label="loc_us-gaap_AccruedLiabilitiesFairValueDisclosure" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_SCLX_AccruedExpenses" xlink:to="loc_us-gaap_AccruedLiabilitiesFairValueDisclosure" use="optional" order="5" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccountsPayableAndOtherAccruedLiabilities" xlink:label="loc_us-gaap_AccountsPayableAndOtherAccruedLiabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_SCLX_AccruedExpenses" xlink:to="loc_us-gaap_AccountsPayableAndOtherAccruedLiabilities" use="optional" order="6" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/BalanceSheetComponentsScheduleOfPropertyAndEquipmentDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:label="loc_us-gaap_PropertyPlantAndEquipmentNet" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PropertyPlantAndEquipmentGross" xlink:label="loc_us-gaap_PropertyPlantAndEquipmentGross" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_PropertyPlantAndEquipmentNet" xlink:to="loc_us-gaap_PropertyPlantAndEquipmentGross" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" xlink:label="loc_us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_PropertyPlantAndEquipmentNet" xlink:to="loc_us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" use="optional" order="2" weight="-1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/CommitmentsAndContingenciesScheduleOfLeaseMaturitiesOfLeaseLiabilitiesDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" use="optional" order="3" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/CommitmentsAndContingenciesScheduleOfLeaseMaturitiesOfLeaseLiabilitiesDetailsAlternate1">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingLeaseLiability" xlink:label="loc_us-gaap_OperatingLeaseLiability" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="loc_us-gaap_OperatingLeaseLiability" use="optional" order="5" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/CondensedConsolidatedStatementsOfCashFlows">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:label="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_AcquisitionConsiderationPaidInCashForRomegIntangibleAssetAcquisition" xlink:label="loc_SCLX_AcquisitionConsiderationPaidInCashForRomegIntangibleAssetAcquisition" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_SCLX_AcquisitionConsiderationPaidInCashForRomegIntangibleAssetAcquisition" use="optional" order="2" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_PurchaseOfEquitySecurities" xlink:label="loc_SCLX_PurchaseOfEquitySecurities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_SCLX_PurchaseOfEquitySecurities" use="optional" order="3" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_PurchaseOfConvertiblePromissoryNote" xlink:label="loc_SCLX_PurchaseOfConvertiblePromissoryNote" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_SCLX_PurchaseOfConvertiblePromissoryNote" use="optional" order="4" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:label="loc_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="loc_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" use="optional" order="5" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" use="optional" order="6" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInAccountsReceivable" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsReceivable" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsReceivable" use="optional" order="7" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetIncomeLoss" xlink:label="loc_us-gaap_NetIncomeLoss" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_NetIncomeLoss" use="optional" order="8" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DepreciationDepletionAndAmortization" xlink:label="loc_us-gaap_DepreciationDepletionAndAmortization" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_DepreciationDepletionAndAmortization" use="optional" order="9" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInInventories" xlink:label="loc_us-gaap_IncreaseDecreaseInInventories" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInInventories" use="optional" order="10" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AmortizationOfFinancingCostsAndDiscounts" xlink:label="loc_us-gaap_AmortizationOfFinancingCostsAndDiscounts" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_AmortizationOfFinancingCostsAndDiscounts" use="optional" order="11" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInPrepaidExpensesOther" xlink:label="loc_us-gaap_IncreaseDecreaseInPrepaidExpensesOther" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInPrepaidExpensesOther" use="optional" order="12" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_NonCashOperatingLeaseCost" xlink:label="loc_SCLX_NonCashOperatingLeaseCost" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_SCLX_NonCashOperatingLeaseCost" use="optional" order="13" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOtherNoncurrentAssets" xlink:label="loc_us-gaap_IncreaseDecreaseInOtherNoncurrentAssets" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInOtherNoncurrentAssets" use="optional" order="14" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensation" xlink:label="loc_us-gaap_ShareBasedCompensation" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_ShareBasedCompensation" use="optional" order="15" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInAccountsPayableTrade" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsPayableTrade" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsPayableTrade" use="optional" order="16" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromInsuranceSettlementOperatingActivities" xlink:label="loc_us-gaap_ProceedsFromInsuranceSettlementOperatingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_ProceedsFromInsuranceSettlementOperatingActivities" use="optional" order="17" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_IncreaseDecreaseInAccruedPayroll" xlink:label="loc_SCLX_IncreaseDecreaseInAccruedPayroll" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_SCLX_IncreaseDecreaseInAccruedPayroll" use="optional" order="18" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DerivativeGainLossOnDerivativeNet" xlink:label="loc_us-gaap_DerivativeGainLossOnDerivativeNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_DerivativeGainLossOnDerivativeNet" use="optional" order="19" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInAccountsPayableAndAccruedLiabilities" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsPayableAndAccruedLiabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsPayableAndAccruedLiabilities" use="optional" order="20" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WriteOffOfDeferredDebtIssuanceCost" xlink:label="loc_us-gaap_WriteOffOfDeferredDebtIssuanceCost" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_WriteOffOfDeferredDebtIssuanceCost" use="optional" order="21" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_IncreaseDecreaseInAccruedRebatesAndFees" xlink:label="loc_SCLX_IncreaseDecreaseInAccruedRebatesAndFees" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_SCLX_IncreaseDecreaseInAccruedRebatesAndFees" use="optional" order="22" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_ChangeInFairValueOfDebtAndLiabilityInstruments" xlink:label="loc_SCLX_ChangeInFairValueOfDebtAndLiabilityInstruments" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_SCLX_ChangeInFairValueOfDebtAndLiabilityInstruments" use="optional" order="23" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOperatingLeaseLiability" xlink:label="loc_us-gaap_IncreaseDecreaseInOperatingLeaseLiability" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_IncreaseDecreaseInOperatingLeaseLiability" use="optional" order="24" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_AllowancesForCreditLosses" xlink:label="loc_SCLX_AllowancesForCreditLosses" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_SCLX_AllowancesForCreditLosses" use="optional" order="25" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_OtherLongTermLiabilities" xlink:label="loc_SCLX_OtherLongTermLiabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_SCLX_OtherLongTermLiabilities" use="optional" order="26" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherOperatingActivitiesCashFlowStatement" xlink:label="loc_us-gaap_OtherOperatingActivitiesCashFlowStatement" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="loc_us-gaap_OtherOperatingActivitiesCashFlowStatement" use="optional" order="27" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:label="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" use="optional" order="28" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_ProceedsFromIssuanceOfSharesUnderStandbyEquityPurchaseAgreementsAndAtmSalesAgreement" xlink:label="loc_SCLX_ProceedsFromIssuanceOfSharesUnderStandbyEquityPurchaseAgreementsAndAtmSalesAgreement" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_ProceedsFromIssuanceOfSharesUnderStandbyEquityPurchaseAgreementsAndAtmSalesAgreement" use="optional" order="29" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromConvertibleDebt" xlink:label="loc_us-gaap_ProceedsFromConvertibleDebt" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_ProceedsFromConvertibleDebt" use="optional" order="30" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_ProceedsFromIssuanceOfRevolvingFacility" xlink:label="loc_SCLX_ProceedsFromIssuanceOfRevolvingFacility" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_ProceedsFromIssuanceOfRevolvingFacility" use="optional" order="31" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_ProceedsFromIssuanceOfFsfDeposit" xlink:label="loc_SCLX_ProceedsFromIssuanceOfFsfDeposit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_ProceedsFromIssuanceOfFsfDeposit" use="optional" order="32" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromIssuanceOfDebt" xlink:label="loc_us-gaap_ProceedsFromIssuanceOfDebt" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_ProceedsFromIssuanceOfDebt" use="optional" order="33" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_RepaymentOfRevolvingFacility" xlink:label="loc_SCLX_RepaymentOfRevolvingFacility" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_RepaymentOfRevolvingFacility" use="optional" order="34" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RepaymentsOfDebt" xlink:label="loc_us-gaap_RepaymentsOfDebt" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_RepaymentsOfDebt" use="optional" order="35" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsForRepurchaseOfWarrants" xlink:label="loc_us-gaap_PaymentsForRepurchaseOfWarrants" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_PaymentsForRepurchaseOfWarrants" use="optional" order="36" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_TransactionCostsPaidRelatedToTheRecapitalizationTransaction" xlink:label="loc_SCLX_TransactionCostsPaidRelatedToTheRecapitalizationTransaction" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_TransactionCostsPaidRelatedToTheRecapitalizationTransaction" use="optional" order="37" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RepaymentsOfConvertibleDebt" xlink:label="loc_us-gaap_RepaymentsOfConvertibleDebt" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_RepaymentsOfConvertibleDebt" use="optional" order="38" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_RepaymentOfDebt" xlink:label="loc_SCLX_RepaymentOfDebt" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_RepaymentOfDebt" use="optional" order="39" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsOfDebtIssuanceCosts" xlink:label="loc_us-gaap_PaymentsOfDebtIssuanceCosts" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_PaymentsOfDebtIssuanceCosts" use="optional" order="40" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_DisbursementOfFunds" xlink:label="loc_SCLX_DisbursementOfFunds" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_DisbursementOfFunds" use="optional" order="41" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AcceleratedShareRepurchasesAdjustmentToRecordedAmount" xlink:label="loc_us-gaap_AcceleratedShareRepurchasesAdjustmentToRecordedAmount" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_AcceleratedShareRepurchasesAdjustmentToRecordedAmount" use="optional" order="42" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_TransactionCostsPaidInConnectionWithShareRepurchase" xlink:label="loc_SCLX_TransactionCostsPaidInConnectionWithShareRepurchase" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_TransactionCostsPaidInConnectionWithShareRepurchase" use="optional" order="43" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_ExciseTaxPaidInConnectionWithShareRepurchase" xlink:label="loc_SCLX_ExciseTaxPaidInConnectionWithShareRepurchase" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_ExciseTaxPaidInConnectionWithShareRepurchase" use="optional" order="44" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromIssuanceOfWarrants" xlink:label="loc_us-gaap_ProceedsFromIssuanceOfWarrants" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_ProceedsFromIssuanceOfWarrants" use="optional" order="45" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsOfStockIssuanceCosts" xlink:label="loc_us-gaap_PaymentsOfStockIssuanceCosts" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_PaymentsOfStockIssuanceCosts" use="optional" order="46" weight="-1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_PaymentsOfDeferredTransactionCostsRelatedToSemnurMerger" xlink:label="loc_SCLX_PaymentsOfDeferredTransactionCostsRelatedToSemnurMerger" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_SCLX_PaymentsOfDeferredTransactionCostsRelatedToSemnurMerger" use="optional" order="47" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromStockOptionsExercised" xlink:label="loc_us-gaap_ProceedsFromStockOptionsExercised" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="loc_us-gaap_ProceedsFromStockOptionsExercised" use="optional" order="48" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/CondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetIncomeLoss" xlink:label="loc_us-gaap_NetIncomeLoss" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetIncomeLoss" xlink:to="loc_us-gaap_IncomeTaxExpenseBenefit" use="optional" order="1" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NetIncomeLoss" xlink:to="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NonoperatingIncomeExpense" xlink:label="loc_us-gaap_NonoperatingIncomeExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:to="loc_us-gaap_NonoperatingIncomeExpense" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DerivativeGainLossOnDerivativeNet" xlink:label="loc_us-gaap_DerivativeGainLossOnDerivativeNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense" xlink:to="loc_us-gaap_DerivativeGainLossOnDerivativeNet" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_ChangeInFairValueOfDebtAndLiabilityInstruments" xlink:label="loc_SCLX_ChangeInFairValueOfDebtAndLiabilityInstruments" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense" xlink:to="loc_SCLX_ChangeInFairValueOfDebtAndLiabilityInstruments" use="optional" order="5" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_InterestExpenseNonoperating" xlink:label="loc_us-gaap_InterestExpenseNonoperating" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense" xlink:to="loc_us-gaap_InterestExpenseNonoperating" use="optional" order="6" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" xlink:label="loc_us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense" xlink:to="loc_us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" use="optional" order="7" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingIncomeLoss" xlink:label="loc_us-gaap_OperatingIncomeLoss" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:to="loc_us-gaap_OperatingIncomeLoss" use="optional" order="8" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingCostsAndExpenses" xlink:label="loc_us-gaap_OperatingCostsAndExpenses" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingIncomeLoss" xlink:to="loc_us-gaap_OperatingCostsAndExpenses" use="optional" order="9" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CostOfRevenue" xlink:label="loc_us-gaap_CostOfRevenue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingCostsAndExpenses" xlink:to="loc_us-gaap_CostOfRevenue" use="optional" order="10" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:label="loc_us-gaap_ResearchAndDevelopmentExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingCostsAndExpenses" xlink:to="loc_us-gaap_ResearchAndDevelopmentExpense" use="optional" order="11" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SellingGeneralAndAdministrativeExpense" xlink:label="loc_us-gaap_SellingGeneralAndAdministrativeExpense" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingCostsAndExpenses" xlink:to="loc_us-gaap_SellingGeneralAndAdministrativeExpense" use="optional" order="12" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AmortizationOfIntangibleAssets" xlink:label="loc_us-gaap_AmortizationOfIntangibleAssets" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingCostsAndExpenses" xlink:to="loc_us-gaap_AmortizationOfIntangibleAssets" use="optional" order="13" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsForLegalSettlements" xlink:label="loc_us-gaap_PaymentsForLegalSettlements" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingCostsAndExpenses" xlink:to="loc_us-gaap_PaymentsForLegalSettlements" use="optional" order="14" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Revenues" xlink:label="loc_us-gaap_Revenues" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingIncomeLoss" xlink:to="loc_us-gaap_Revenues" use="optional" order="15" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/CondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherComprehensiveIncomeLossNetOfTax" xlink:label="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTax" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherComprehensiveIncomeLossPensionAndOtherPostretirementBenefitPlansAdjustmentNetOfTax" xlink:label="loc_us-gaap_OtherComprehensiveIncomeLossPensionAndOtherPostretirementBenefitPlansAdjustmentNetOfTax" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_OtherComprehensiveIncomeLossNetOfTax" xlink:to="loc_us-gaap_OtherComprehensiveIncomeLossPensionAndOtherPostretirementBenefitPlansAdjustmentNetOfTax" use="optional" order="16" weight="-1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LiabilitiesAndStockholdersEquity" xlink:label="loc_us-gaap_LiabilitiesAndStockholdersEquity" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockholdersEquity" xlink:label="loc_us-gaap_StockholdersEquity" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="loc_us-gaap_StockholdersEquity" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PreferredStockValue" xlink:label="loc_us-gaap_PreferredStockValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_PreferredStockValue" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CommonStockValue" xlink:label="loc_us-gaap_CommonStockValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_CommonStockValue" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdditionalPaidInCapital" xlink:label="loc_us-gaap_AdditionalPaidInCapital" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_AdditionalPaidInCapital" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" xlink:label="loc_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" use="optional" order="5" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:label="loc_us-gaap_RetainedEarningsAccumulatedDeficit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_RetainedEarningsAccumulatedDeficit" use="optional" order="6" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_TreasuryStockValue" xlink:label="loc_us-gaap_TreasuryStockValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity" xlink:to="loc_us-gaap_TreasuryStockValue" use="optional" order="7" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Liabilities" xlink:label="loc_us-gaap_Liabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="loc_us-gaap_Liabilities" use="optional" order="8" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LiabilitiesCurrent" xlink:label="loc_us-gaap_LiabilitiesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_us-gaap_LiabilitiesCurrent" use="optional" order="9" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccountsPayableCurrent" xlink:label="loc_us-gaap_AccountsPayableCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_AccountsPayableCurrent" use="optional" order="10" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccruedSalariesCurrent" xlink:label="loc_us-gaap_AccruedSalariesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_AccruedSalariesCurrent" use="optional" order="11" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherAccruedLiabilitiesCurrent" xlink:label="loc_us-gaap_OtherAccruedLiabilitiesCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_OtherAccruedLiabilitiesCurrent" use="optional" order="12" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_AccruedExpenses" xlink:label="loc_SCLX_AccruedExpenses" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_SCLX_AccruedExpenses" use="optional" order="13" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_CurrentPortionOfDeferredConsideration" xlink:label="loc_SCLX_CurrentPortionOfDeferredConsideration" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_SCLX_CurrentPortionOfDeferredConsideration" use="optional" order="14" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtCurrent" xlink:label="loc_us-gaap_DebtCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_DebtCurrent" use="optional" order="15" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_PurchasedRevenueLiabilityCurrent" xlink:label="loc_SCLX_PurchasedRevenueLiabilityCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_SCLX_PurchasedRevenueLiabilityCurrent" use="optional" order="16" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingLeaseLiabilityCurrent" xlink:label="loc_us-gaap_OperatingLeaseLiabilityCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent" xlink:to="loc_us-gaap_OperatingLeaseLiabilityCurrent" use="optional" order="17" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_LongTermPortionOfDeferredConsideration" xlink:label="loc_SCLX_LongTermPortionOfDeferredConsideration" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_SCLX_LongTermPortionOfDeferredConsideration" use="optional" order="18" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherLongTermDebtNoncurrent" xlink:label="loc_us-gaap_OtherLongTermDebtNoncurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_us-gaap_OtherLongTermDebtNoncurrent" use="optional" order="19" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_PurchasedRevenueLiabilityNoncurrent" xlink:label="loc_SCLX_PurchasedRevenueLiabilityNoncurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_SCLX_PurchasedRevenueLiabilityNoncurrent" use="optional" order="20" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DerivativeLiabilitiesNoncurrent" xlink:label="loc_us-gaap_DerivativeLiabilitiesNoncurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_us-gaap_DerivativeLiabilitiesNoncurrent" use="optional" order="21" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent" xlink:label="loc_us-gaap_OperatingLeaseLiabilityNoncurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_us-gaap_OperatingLeaseLiabilityNoncurrent" use="optional" order="22" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherLiabilitiesNoncurrent" xlink:label="loc_us-gaap_OtherLiabilitiesNoncurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities" xlink:to="loc_us-gaap_OtherLiabilitiesNoncurrent" use="optional" order="23" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/ConsolidatedBalanceSheets">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Assets" xlink:label="loc_us-gaap_Assets" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AssetsCurrent" xlink:label="loc_us-gaap_AssetsCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_AssetsCurrent" use="optional" order="24" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:label="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue" use="optional" order="25" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccountsReceivableNetCurrent" xlink:label="loc_us-gaap_AccountsReceivableNetCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_AccountsReceivableNetCurrent" use="optional" order="26" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_InventoryNet" xlink:label="loc_us-gaap_InventoryNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_InventoryNet" use="optional" order="27" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherPrepaidExpenseCurrent" xlink:label="loc_us-gaap_OtherPrepaidExpenseCurrent" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent" xlink:to="loc_us-gaap_OtherPrepaidExpenseCurrent" use="optional" order="28" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:label="loc_us-gaap_PropertyPlantAndEquipmentNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_PropertyPlantAndEquipmentNet" use="optional" order="29" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingLeaseRightOfUseAsset" xlink:label="loc_us-gaap_OperatingLeaseRightOfUseAsset" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_OperatingLeaseRightOfUseAsset" use="optional" order="30" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IntangibleAssetsNetExcludingGoodwill" xlink:label="loc_us-gaap_IntangibleAssetsNetExcludingGoodwill" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_IntangibleAssetsNetExcludingGoodwill" use="optional" order="31" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Investments" xlink:label="loc_us-gaap_Investments" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_Investments" use="optional" order="32" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Goodwill" xlink:label="loc_us-gaap_Goodwill" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_Goodwill" use="optional" order="33" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AssetsNoncurrentOtherThanNoncurrentInvestmentsAndPropertyPlantAndEquipment" xlink:label="loc_us-gaap_AssetsNoncurrentOtherThanNoncurrentInvestmentsAndPropertyPlantAndEquipment" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_Assets" xlink:to="loc_us-gaap_AssetsNoncurrentOtherThanNoncurrentInvestmentsAndPropertyPlantAndEquipment" use="optional" order="34" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/GoodwillAndIntangibleAssetsEstimatedFutureAmortizationExpenseOfIntangibleAssetsDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsNet" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFive" xlink:label="loc_SCLX_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFive" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_SCLX_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFive" use="optional" order="5" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFour" xlink:label="loc_SCLX_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFour" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet" xlink:to="loc_SCLX_FiniteLivedIntangibleAssetExpectedAmortizationAfterYearFour" use="optional" order="6" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/IncomeTaxesScheduleOfComponentsOfBenefitForIncomeTaxesDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CurrentIncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_CurrentIncomeTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_CurrentIncomeTaxExpenseBenefit" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CurrentFederalTaxExpenseBenefit" xlink:label="loc_us-gaap_CurrentFederalTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CurrentIncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_CurrentFederalTaxExpenseBenefit" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CurrentStateAndLocalTaxExpenseBenefit" xlink:label="loc_us-gaap_CurrentStateAndLocalTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CurrentIncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_CurrentStateAndLocalTaxExpenseBenefit" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredIncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_DeferredIncomeTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_DeferredIncomeTaxExpenseBenefit" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredFederalIncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_DeferredFederalIncomeTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredIncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_DeferredFederalIncomeTaxExpenseBenefit" use="optional" order="5" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredIncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_DeferredStateAndLocalIncomeTaxExpenseBenefit" use="optional" order="6" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate" xlink:label="loc_us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationChangeInEnactedTaxRate" use="optional" order="7" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance" xlink:label="loc_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationChangeInDeferredTaxAssetsValuationAllowance" use="optional" order="8" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/IncomeTaxesScheduleOfDeferredTaxLiabilitiesAndRelatedValuationAllowanceDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsLiabilitiesNet" xlink:label="loc_us-gaap_DeferredTaxAssetsLiabilitiesNet" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsNet" xlink:label="loc_us-gaap_DeferredTaxAssetsNet" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsLiabilitiesNet" xlink:to="loc_us-gaap_DeferredTaxAssetsNet" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsGross" xlink:label="loc_us-gaap_DeferredTaxAssetsGross" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_us-gaap_DeferredTaxAssetsGross" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" xlink:label="loc_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_us-gaap_DeferredTaxAssetsOperatingLossCarryforwards" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_DeferredTaxAssetsDebtRelatedInterest" xlink:label="loc_SCLX_DeferredTaxAssetsDebtRelatedInterest" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_SCLX_DeferredTaxAssetsDebtRelatedInterest" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsInProcessResearchAndDevelopment" xlink:label="loc_us-gaap_DeferredTaxAssetsInProcessResearchAndDevelopment" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_us-gaap_DeferredTaxAssetsInProcessResearchAndDevelopment" use="optional" order="5" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsTaxCreditCarryforwards" xlink:label="loc_us-gaap_DeferredTaxAssetsTaxCreditCarryforwards" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_us-gaap_DeferredTaxAssetsTaxCreditCarryforwards" use="optional" order="6" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" xlink:label="loc_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_us-gaap_DeferredTaxAssetsTaxDeferredExpenseCompensationAndBenefitsShareBasedCompensationCost" use="optional" order="7" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_DeferredTaxAssetsAccruedExpenseAndReserves" xlink:label="loc_SCLX_DeferredTaxAssetsAccruedExpenseAndReserves" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_SCLX_DeferredTaxAssetsAccruedExpenseAndReserves" use="optional" order="8" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_DeferredTaxAssetsPurchasedRevenueLiability" xlink:label="loc_SCLX_DeferredTaxAssetsPurchasedRevenueLiability" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_SCLX_DeferredTaxAssetsPurchasedRevenueLiability" use="optional" order="9" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_DeferredTaxAssetsOperatingLeaseLiabilities" xlink:label="loc_SCLX_DeferredTaxAssetsOperatingLeaseLiabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_SCLX_DeferredTaxAssetsOperatingLeaseLiabilities" use="optional" order="10" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsOther" xlink:label="loc_us-gaap_DeferredTaxAssetsOther" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsGross" xlink:to="loc_us-gaap_DeferredTaxAssetsOther" use="optional" order="11" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxAssetsValuationAllowance" xlink:label="loc_us-gaap_DeferredTaxAssetsValuationAllowance" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsNet" xlink:to="loc_us-gaap_DeferredTaxAssetsValuationAllowance" use="optional" order="12" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxLiabilities" xlink:label="loc_us-gaap_DeferredTaxLiabilities" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxAssetsLiabilitiesNet" xlink:to="loc_us-gaap_DeferredTaxLiabilities" use="optional" order="13" weight="-1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxLiabilitiesGoodwillAndIntangibleAssetsIntangibleAssets" xlink:label="loc_us-gaap_DeferredTaxLiabilitiesGoodwillAndIntangibleAssetsIntangibleAssets" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxLiabilities" xlink:to="loc_us-gaap_DeferredTaxLiabilitiesGoodwillAndIntangibleAssetsIntangibleAssets" use="optional" order="14" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DeferredTaxLiabilitiesLeasingArrangements" xlink:label="loc_us-gaap_DeferredTaxLiabilitiesLeasingArrangements" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_DeferredTaxLiabilities" xlink:to="loc_us-gaap_DeferredTaxLiabilitiesLeasingArrangements" use="optional" order="15" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/IncomeTaxesScheduleOfEffectiveIncomeTaxRateReconciliationDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate" xlink:label="loc_us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationIncomeTaxExpenseBenefitAtFederalStatutoryIncomeTaxRate" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_IncomeTaxReconciliationValuationAllowanceAtFederalStatutoryIncomeTaxRate" xlink:label="loc_SCLX_IncomeTaxReconciliationValuationAllowanceAtFederalStatutoryIncomeTaxRate" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_SCLX_IncomeTaxReconciliationValuationAllowanceAtFederalStatutoryIncomeTaxRate" use="optional" order="2" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost" xlink:label="loc_us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationNondeductibleExpenseShareBasedCompensationCost" use="optional" order="3" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_IncomeTaxReconciliationAcquisitionRelatedCharges" xlink:label="loc_SCLX_IncomeTaxReconciliationAcquisitionRelatedCharges" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_SCLX_IncomeTaxReconciliationAcquisitionRelatedCharges" use="optional" order="4" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes" xlink:label="loc_us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationPriorYearIncomeTaxes" use="optional" order="5" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes" xlink:label="loc_us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationStateAndLocalIncomeTaxes" use="optional" order="6" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_EffectiveIncomeTaxRateReconciliationChangeInFairValueOfConvertibleDebenturesAmount" xlink:label="loc_SCLX_EffectiveIncomeTaxRateReconciliationChangeInFairValueOfConvertibleDebenturesAmount" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_SCLX_EffectiveIncomeTaxRateReconciliationChangeInFairValueOfConvertibleDebenturesAmount" use="optional" order="7" weight="1" />
<loc xlink:type="locator" xlink:href="sclx-20241231.xsd#sclx_EffectiveIncomeTaxRateReconciliationChangeInTaxRatesAmount" xlink:label="loc_SCLX_EffectiveIncomeTaxRateReconciliationChangeInTaxRatesAmount" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_SCLX_EffectiveIncomeTaxRateReconciliationChangeInTaxRatesAmount" use="optional" order="8" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxReconciliationOtherAdjustments" xlink:label="loc_us-gaap_IncomeTaxReconciliationOtherAdjustments" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeTaxExpenseBenefit" xlink:to="loc_us-gaap_IncomeTaxReconciliationOtherAdjustments" use="optional" order="9" weight="1" />
</calculationLink>
<calculationLink xlink:type="extended" xlink:role="http://www.scilexholding.com/role/NatureOfOperationsAndBasisOfPresentationScheduleOfCashAndCashEquivalentsDetails">
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:label="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:label="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:to="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue" use="optional" order="1" weight="1" />
<loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RestrictedCashAndCashEquivalents" xlink:label="loc_us-gaap_RestrictedCashAndCashEquivalents" />
<calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:to="loc_us-gaap_RestrictedCashAndCashEquivalents" use="optional" order="2" weight="1" />
</calculationLink>
</linkbase>
