<?xml version="1.0" encoding="UTF-8"?>

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2026 Workiva-->
<!--r:019d685f-63a9-7d2c-828a-6545319712d9,g:ea22fc1e-238b-4dee-9c31-51961c17795a-->
<xs:schema xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:oncy="http://www.oncolyticsbiotech.com/20260331" xmlns:xbrli="http://www.xbrl.org/2003/instance" xmlns:dtr-types="http://www.xbrl.org/dtr/type/2024-01-31" attributeFormDefault="unqualified" elementFormDefault="qualified" targetNamespace="http://www.oncolyticsbiotech.com/20260331">
  <xs:import namespace="http://fasb.org/srt/2025" schemaLocation="https://xbrl.fasb.org/srt/2025/elts/srt-2025.xsd"/>
  <xs:import namespace="http://fasb.org/us-gaap/2025" schemaLocation="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd"/>
  <xs:import namespace="http://www.xbrl.org/2003/instance" schemaLocation="http://www.xbrl.org/2003/xbrl-instance-2003-12-31.xsd"/>
  <xs:import namespace="http://www.xbrl.org/2003/linkbase" schemaLocation="http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd"/>
  <xs:import namespace="http://www.xbrl.org/dtr/type/2024-01-31" schemaLocation="https://www.xbrl.org/dtr/type/2024-01-31/types.xsd"/>
  <xs:import namespace="http://xbrl.sec.gov/dei/2025" schemaLocation="https://xbrl.sec.gov/dei/2025/dei-2025.xsd"/>
  <xs:import namespace="http://xbrl.sec.gov/ecd/2025" schemaLocation="https://xbrl.sec.gov/ecd/2025/ecd-2025.xsd"/>
  <xs:annotation>
    <xs:appinfo>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="oncy-20260331_pre.xml" xlink:role="http://www.xbrl.org/2003/role/presentationLinkbaseRef" xlink:type="simple"/>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="oncy-20260331_def.xml" xlink:role="http://www.xbrl.org/2003/role/definitionLinkbaseRef" xlink:type="simple"/>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="oncy-20260331_lab.xml" xlink:role="http://www.xbrl.org/2003/role/labelLinkbaseRef" xlink:type="simple"/>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="oncy-20260331_cal.xml" xlink:role="http://www.xbrl.org/2003/role/calculationLinkbaseRef" xlink:type="simple"/>
      <link:roleType id="CoverPage" roleURI="http://www.oncolyticsbiotech.com/role/CoverPage">
        <link:definition>0000001 - Document - Cover Page</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CONDENSEDCONSOLIDATEDBALANCESHEETS" roleURI="http://www.oncolyticsbiotech.com/role/CONDENSEDCONSOLIDATEDBALANCESHEETS">
        <link:definition>9952151 - Statement - CONDENSED CONSOLIDATED BALANCE SHEETS</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CONDENSEDCONSOLIDATEDBALANCESHEETSParenthetical" roleURI="http://www.oncolyticsbiotech.com/role/CONDENSEDCONSOLIDATEDBALANCESHEETSParenthetical">
        <link:definition>9952152 - Statement - CONDENSED CONSOLIDATED BALANCE SHEETS (Parenthetical)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CONSOLIDATEDSTATEMENTSOFOPERATIONSANDCOMPREHENSIVELOSSunaudited" roleURI="http://www.oncolyticsbiotech.com/role/CONSOLIDATEDSTATEMENTSOFOPERATIONSANDCOMPREHENSIVELOSSunaudited">
        <link:definition>9952153 - Statement - CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (unaudited)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CONDENSEDCONSOLIDATEDSTATEMENTSOFCHANGESINSTOCKHOLDERSDEFICITEQUITYunaudited" roleURI="http://www.oncolyticsbiotech.com/role/CONDENSEDCONSOLIDATEDSTATEMENTSOFCHANGESINSTOCKHOLDERSDEFICITEQUITYunaudited">
        <link:definition>9952154 - Statement - CONDENSED CONSOLIDATED STATEMENTS OF CHANGES IN STOCKHOLDERS&#8217; (DEFICIT) EQUITY (unaudited)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CONSOLIDATEDSTATEMENTSOFCASHFLOWSunaudited" roleURI="http://www.oncolyticsbiotech.com/role/CONSOLIDATEDSTATEMENTSOFCASHFLOWSunaudited">
        <link:definition>9952155 - Statement - CONSOLIDATED STATEMENTS OF CASH FLOWS (unaudited)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="NatureofOperations" roleURI="http://www.oncolyticsbiotech.com/role/NatureofOperations">
        <link:definition>9952156 - Disclosure - Nature of Operations</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BasisofPresentation" roleURI="http://www.oncolyticsbiotech.com/role/BasisofPresentation">
        <link:definition>9952157 - Disclosure - Basis of Presentation</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SummaryofSignificantAccountingPolicies" roleURI="http://www.oncolyticsbiotech.com/role/SummaryofSignificantAccountingPolicies">
        <link:definition>9952158 - Disclosure - Summary of Significant Accounting Policies</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BalanceSheetDetails" roleURI="http://www.oncolyticsbiotech.com/role/BalanceSheetDetails">
        <link:definition>9952159 - Disclosure - Balance Sheet Details</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="Leases" roleURI="http://www.oncolyticsbiotech.com/role/Leases">
        <link:definition>9952160 - Disclosure - Leases</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonShares" roleURI="http://www.oncolyticsbiotech.com/role/CommonShares">
        <link:definition>9952161 - Disclosure - Common Shares</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensation" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensation">
        <link:definition>9952162 - Disclosure - Stock-Based Compensation</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="NetLossPerShare" roleURI="http://www.oncolyticsbiotech.com/role/NetLossPerShare">
        <link:definition>9952163 - Disclosure - Net Loss Per Share</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ContractLiability" roleURI="http://www.oncolyticsbiotech.com/role/ContractLiability">
        <link:definition>9952164 - Disclosure - Contract Liability</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingencies" roleURI="http://www.oncolyticsbiotech.com/role/CommitmentsandContingencies">
        <link:definition>9952165 - Disclosure - Commitments and Contingencies</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SegmentInformation" roleURI="http://www.oncolyticsbiotech.com/role/SegmentInformation">
        <link:definition>9952166 - Disclosure - Segment Information</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SubsequentEvents" roleURI="http://www.oncolyticsbiotech.com/role/SubsequentEvents">
        <link:definition>9952167 - Disclosure - Subsequent Events</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SummaryofSignificantAccountingPoliciesPolicies" roleURI="http://www.oncolyticsbiotech.com/role/SummaryofSignificantAccountingPoliciesPolicies">
        <link:definition>9955511 - Disclosure - Summary of Significant Accounting Policies (Policies)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BalanceSheetDetailsTables" roleURI="http://www.oncolyticsbiotech.com/role/BalanceSheetDetailsTables">
        <link:definition>9955512 - Disclosure - Balance Sheet Details (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="LeasesTables" roleURI="http://www.oncolyticsbiotech.com/role/LeasesTables">
        <link:definition>9955513 - Disclosure - Leases (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationTables" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationTables">
        <link:definition>9955514 - Disclosure - Stock-Based Compensation (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="NetLossPerShareTables" roleURI="http://www.oncolyticsbiotech.com/role/NetLossPerShareTables">
        <link:definition>9955515 - Disclosure - Net Loss Per Share (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ContractLiabilityTables" roleURI="http://www.oncolyticsbiotech.com/role/ContractLiabilityTables">
        <link:definition>9955516 - Disclosure - Contract Liability (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SegmentInformationTables" roleURI="http://www.oncolyticsbiotech.com/role/SegmentInformationTables">
        <link:definition>9955517 - Disclosure - Segment Information (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="NatureofOperationsDetails" roleURI="http://www.oncolyticsbiotech.com/role/NatureofOperationsDetails">
        <link:definition>9955518 - Disclosure - Nature of Operations (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BalanceSheetDetailsScheduleofPrepaidExpensesDetails" roleURI="http://www.oncolyticsbiotech.com/role/BalanceSheetDetailsScheduleofPrepaidExpensesDetails">
        <link:definition>9955519 - Disclosure - Balance Sheet Details - Schedule of Prepaid Expenses (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BalanceSheetDetailsScheduleofAccruedLiabilitiesDetails" roleURI="http://www.oncolyticsbiotech.com/role/BalanceSheetDetailsScheduleofAccruedLiabilitiesDetails">
        <link:definition>9955520 - Disclosure - Balance Sheet Details - Schedule of Accrued Liabilities (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BalanceSheetDetailsNarrativeDetails" roleURI="http://www.oncolyticsbiotech.com/role/BalanceSheetDetailsNarrativeDetails">
        <link:definition>9955521 - Disclosure - Balance Sheet Details - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="LeasesNarrativeDetails" roleURI="http://www.oncolyticsbiotech.com/role/LeasesNarrativeDetails">
        <link:definition>9955522 - Disclosure - Leases - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="LeasesMaturitiesofOperatingLeaseLiabilitiesDetails" roleURI="http://www.oncolyticsbiotech.com/role/LeasesMaturitiesofOperatingLeaseLiabilitiesDetails">
        <link:definition>9955523 - Disclosure - Leases - Maturities of Operating Lease Liabilities (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="LeasesMaturitiesofOperatingLeaseLiabilitiesDetails_1" roleURI="http://www.oncolyticsbiotech.com/role/LeasesMaturitiesofOperatingLeaseLiabilitiesDetails_1">
        <link:definition>9955523 - Disclosure - Leases - Maturities of Operating Lease Liabilities (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonSharesAuthorizedShareCapitalDetails" roleURI="http://www.oncolyticsbiotech.com/role/CommonSharesAuthorizedShareCapitalDetails">
        <link:definition>9955524 - Disclosure - Common Shares - Authorized Share Capital (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonSharesAttheMarketOfferingAgreementsDetails" roleURI="http://www.oncolyticsbiotech.com/role/CommonSharesAttheMarketOfferingAgreementsDetails">
        <link:definition>9955525 - Disclosure - Common Shares - At-the-Market Offering Agreements (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonSharesConsultantServicesSharesIssuedDetails" roleURI="http://www.oncolyticsbiotech.com/role/CommonSharesConsultantServicesSharesIssuedDetails">
        <link:definition>9955526 - Disclosure - Common Shares - Consultant Services Shares Issued (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonSharesCompensationWarrantsDetails" roleURI="http://www.oncolyticsbiotech.com/role/CommonSharesCompensationWarrantsDetails">
        <link:definition>9955527 - Disclosure - Common Shares - Compensation Warrants (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonSharesWarrantsDetails" roleURI="http://www.oncolyticsbiotech.com/role/CommonSharesWarrantsDetails">
        <link:definition>9955528 - Disclosure - Common Shares - Warrants (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationNarrativeDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationNarrativeDetails">
        <link:definition>9955529 - Disclosure - Stock-Based Compensation - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleofStockBasedCompensationExpenseDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleofStockBasedCompensationExpenseDetails">
        <link:definition>9955530 - Disclosure - Stock-Based Compensation - Schedule of Stock-Based Compensation Expense (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleofStockOptionsSubjecttoServiceConditionsDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleofStockOptionsSubjecttoServiceConditionsDetails">
        <link:definition>9955531 - Disclosure - Stock-Based Compensation - Schedule of Stock Options Subject to Service Conditions (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleofStockOptionsSubjecttoPerformanceConditionsDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleofStockOptionsSubjecttoPerformanceConditionsDetails">
        <link:definition>9955532 - Disclosure - Stock-Based Compensation - Schedule of Stock Options Subject to Performance Conditions (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleofStockOptionsOutstandingandExercisableDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleofStockOptionsOutstandingandExercisableDetails">
        <link:definition>9955533 - Disclosure - Stock-Based Compensation - Schedule of Stock Options, Outstanding and Exercisable (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleofStockOptionValuationAssumptionsDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleofStockOptionValuationAssumptionsDetails">
        <link:definition>9955534 - Disclosure - Stock-Based Compensation - Schedule of Stock Option, Valuation Assumptions (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleStockOptionLiabilityDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleStockOptionLiabilityDetails">
        <link:definition>9955535 - Disclosure - Stock-Based Compensation - Schedule Stock Option Liability (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockBasedCompensationScheduleofRestrictedStockUnitsDetails" roleURI="http://www.oncolyticsbiotech.com/role/StockBasedCompensationScheduleofRestrictedStockUnitsDetails">
        <link:definition>9955536 - Disclosure - Stock-Based Compensation - Schedule of Restricted Stock Units (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="NetLossPerShareScheduleofNetLossPerShareDetails" roleURI="http://www.oncolyticsbiotech.com/role/NetLossPerShareScheduleofNetLossPerShareDetails">
        <link:definition>9955537 - Disclosure - Net Loss Per Share - Schedule of Net Loss Per Share (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="NetLossPerShareScheduleofAntidilutiveSecuritiesExcludedfromComputationofNetLossPerShareDetails" roleURI="http://www.oncolyticsbiotech.com/role/NetLossPerShareScheduleofAntidilutiveSecuritiesExcludedfromComputationofNetLossPerShareDetails">
        <link:definition>9955538 - Disclosure - Net Loss Per Share - Schedule of Antidilutive Securities Excluded from Computation of Net Loss Per Share (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ContractLiabilityDetails" roleURI="http://www.oncolyticsbiotech.com/role/ContractLiabilityDetails">
        <link:definition>9955539 - Disclosure - Contract Liability (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ContractLiabilityDetails_1" roleURI="http://www.oncolyticsbiotech.com/role/ContractLiabilityDetails_1">
        <link:definition>9955539 - Disclosure - Contract Liability (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentandContingenciesDetails" roleURI="http://www.oncolyticsbiotech.com/role/CommitmentandContingenciesDetails">
        <link:definition>9955540 - Disclosure - Commitment and Contingencies (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SegmentInformationNarrativeDetails" roleURI="http://www.oncolyticsbiotech.com/role/SegmentInformationNarrativeDetails">
        <link:definition>9955541 - Disclosure - Segment Information - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SegmentInformationScheduleofSegmentInformationDetails" roleURI="http://www.oncolyticsbiotech.com/role/SegmentInformationScheduleofSegmentInformationDetails">
        <link:definition>9955542 - Disclosure - Segment Information - Schedule of Segment Information (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SubsequentEventsDetails" roleURI="http://www.oncolyticsbiotech.com/role/SubsequentEventsDetails">
        <link:definition>9955543 - Disclosure - Subsequent Events (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
    </xs:appinfo>
  </xs:annotation>
  <xs:element id="oncy_APICShareBasedPaymentArrangementReclassification" abstract="false" name="APICShareBasedPaymentArrangementReclassification" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_NoncashLeaseExpense" abstract="false" name="NoncashLeaseExpense" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_ScheduleOfDeferredCompensationLiabilityTableTextBlock" abstract="false" name="ScheduleOfDeferredCompensationLiabilityTableTextBlock" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:textBlockItemType"/>
  <xs:element id="oncy_PrepaidResearchAndDevelopment" abstract="false" name="PrepaidResearchAndDevelopment" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_PrepaidProfessionalFees" abstract="false" name="PrepaidProfessionalFees" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_AccruedResearchAndDevelopmentCurrent" abstract="false" name="AccruedResearchAndDevelopmentCurrent" nillable="true" xbrli:periodType="instant" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_GrantAssistanceAwardAmount" abstract="false" name="GrantAssistanceAwardAmount" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_ProceedsFromGrantAssistance" abstract="false" name="ProceedsFromGrantAssistance" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_GrantAssistanceLiabilityDecreaseCurrent" abstract="false" name="GrantAssistanceLiabilityDecreaseCurrent" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_CommonStockVotingRightsNumberOfVotesPerCommonShare" abstract="false" name="CommonStockVotingRightsNumberOfVotesPerCommonShare" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="xbrli:integerItemType"/>
  <xs:element id="oncy_October2025AtTheMarketOfferingAgreementMember" abstract="true" name="October2025AtTheMarketOfferingAgreementMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_August2024AtTheMarketOfferingAgreementMember" abstract="true" name="August2024AtTheMarketOfferingAgreementMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_SaleOfStockAuthorizedAmount" abstract="false" name="SaleOfStockAuthorizedAmount" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_SaleOfStockAuthorizedPeriod" abstract="false" name="SaleOfStockAuthorizedPeriod" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="xbrli:durationItemType"/>
  <xs:element id="oncy_ConsultingServiceAgreementsMember" abstract="true" name="ConsultingServiceAgreementsMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_CompensationWarrantMember" abstract="true" name="CompensationWarrantMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ClassOfWarrantOrRightIssued" abstract="false" name="ClassOfWarrantOrRightIssued" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="oncy_WarrantsAndRightsOutstandingThresholdConsecutiveTradingDaysWeightedAveragePrice" abstract="false" name="WarrantsAndRightsOutstandingThresholdConsecutiveTradingDaysWeightedAveragePrice" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="dtr-types:perShareItemType"/>
  <xs:element id="oncy_WarrantsAndRightsOutstandingThresholdConsecutiveTradingDays" abstract="false" name="WarrantsAndRightsOutstandingThresholdConsecutiveTradingDays" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:integerItemType"/>
  <xs:element id="oncy_WarrantsAndRightsOutstandingThresholdTradingDays" abstract="false" name="WarrantsAndRightsOutstandingThresholdTradingDays" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:integerItemType"/>
  <xs:element id="oncy_WarrantsAndRightsOutstandingExpirationPeriod" abstract="false" name="WarrantsAndRightsOutstandingExpirationPeriod" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="xbrli:integerItemType"/>
  <xs:element id="oncy_A2026IncentiveAwardPlanMember" abstract="true" name="A2026IncentiveAwardPlanMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_EquityIncentivePlansMember" abstract="true" name="EquityIncentivePlansMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ShareBasedPaymentArrangementOptionPerformanceConditionMember" abstract="true" name="ShareBasedPaymentArrangementOptionPerformanceConditionMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ShareBasedPaymentArrangementOptionServiceConditionMember" abstract="true" name="ShareBasedPaymentArrangementOptionServiceConditionMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_InducementShareAwardsMember" abstract="true" name="InducementShareAwardsMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_CommonStockCapitalSharesReservedForFutureIssuanceAnnualIncreasePercentage" abstract="false" name="CommonStockCapitalSharesReservedForFutureIssuanceAnnualIncreasePercentage" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="dtr-types:percentItemType"/>
  <xs:element id="oncy_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsThresholdForVestingMinimumAmount" abstract="false" name="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsThresholdForVestingMinimumAmount" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_InducementStockOptionsMember" abstract="true" name="InducementStockOptionsMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ExercisePriceRangeOneMember" abstract="true" name="ExercisePriceRangeOneMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ExercisePriceRangeTwoMember" abstract="true" name="ExercisePriceRangeTwoMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ExercisePriceRangeThreeMember" abstract="true" name="ExercisePriceRangeThreeMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ExercisePriceRangeFourMember" abstract="true" name="ExercisePriceRangeFourMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ExercisePriceRangeFiveMember" abstract="true" name="ExercisePriceRangeFiveMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingAbstract" abstract="true" name="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingAbstract" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:stringItemType"/>
  <xs:element id="oncy_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableAbstract" abstract="true" name="ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsExercisableAbstract" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:stringItemType"/>
  <xs:element id="oncy_ShareBasedPaymentArrangementLiabilityClassifiedOptionMember" abstract="true" name="ShareBasedPaymentArrangementLiabilityClassifiedOptionMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ShareBasedCompensationArrangementByShareBasedPaymentAwardStockOptionLiabilityRollForward" abstract="true" name="ShareBasedCompensationArrangementByShareBasedPaymentAwardStockOptionLiabilityRollForward" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:stringItemType"/>
  <xs:element id="oncy_DeferredCompensationShareBasedArrangementsReclassificationOfLiabilityFromEquity" abstract="false" name="DeferredCompensationShareBasedArrangementsReclassificationOfLiabilityFromEquity" nillable="true" xbrli:periodType="duration" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_DeferredCompensationShareBasedArrangementsShareBasedPaymentArrangementExpense" abstract="false" name="DeferredCompensationShareBasedArrangementsShareBasedPaymentArrangementExpense" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_DeferredCompensationShareBasedArrangementsAdjustmentToLiability" abstract="false" name="DeferredCompensationShareBasedArrangementsAdjustmentToLiability" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_RestrictedStockUnitsAndIncentiveShareAwardsMember" abstract="true" name="RestrictedStockUnitsAndIncentiveShareAwardsMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ContractWithCustomerLiabilityRollForward" abstract="true" name="ContractWithCustomerLiabilityRollForward" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:stringItemType"/>
  <xs:element id="oncy_ContractWithCustomerLiabilityForeignCurrencyTranslationAdjustment" abstract="false" name="ContractWithCustomerLiabilityForeignCurrencyTranslationAdjustment" nillable="true" xbrli:periodType="duration" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_ReportableSegmentMember" abstract="true" name="ReportableSegmentMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="oncy_ResearchAndDevelopmentExpenseClinicalTrial" abstract="false" name="ResearchAndDevelopmentExpenseClinicalTrial" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_ResearchAndDevelopmentExpenseManufacturingAndRelatedProcessDevelopment" abstract="false" name="ResearchAndDevelopmentExpenseManufacturingAndRelatedProcessDevelopment" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_IntellectualPropertyExpense" abstract="false" name="IntellectualPropertyExpense" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_OtherResearchAndDevelopmentExpenseAndOtherGeneralAndAdministrativeExpense" abstract="false" name="OtherResearchAndDevelopmentExpenseAndOtherGeneralAndAdministrativeExpense" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="oncy_SaleOfStockConsiderationReceivedOnTransactionMaximum" abstract="false" name="SaleOfStockConsiderationReceivedOnTransactionMaximum" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
</xs:schema>
