<?xml version="1.0" encoding="utf-8"?>
<!--Generated by DFIN XBRL Instance Document - http://www.dfinsolutions.com/ - Version R3.0 - on 28-April-2023 [09:42:17] {AM}-->
<schema targetNamespace="http://www.zymeworks.com/20221231" elementFormDefault="qualified" xmlns:zyme="http://www.zymeworks.com/20221231" xmlns="http://www.w3.org/2001/XMLSchema" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xbrli="http://www.xbrl.org/2003/instance" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xmlns:xl="http://www.xbrl.org/2003/XLink" xmlns:us-gaap="http://fasb.org/us-gaap/2022" xmlns:country="http://xbrl.sec.gov/country/2022" xmlns:currency="http://xbrl.sec.gov/currency/2022" xmlns:dei="http://xbrl.sec.gov/dei/2022" xmlns:exch="http://xbrl.sec.gov/exch/2022" xmlns:naics="http://xbrl.sec.gov/naics/2022" xmlns:sic="http://xbrl.sec.gov/sic/2022" xmlns:us-types="http://fasb.org/us-types/2022" xmlns:stpr="http://xbrl.sec.gov/stpr/2022" xmlns:deprecated="http://www.xbrl.org/2009/arcrole/fact-explanatoryFact" xmlns:srt="http://fasb.org/srt/2022" xmlns:srt-types="http://fasb.org/srt-types/2022" xmlns:dtr-types="http://www.xbrl.org/dtr/type/2020-01-21" xmlns:us-gaap-supplement="http://fasb.org/us-gaap-sup/2022q3" xmlns:srt-supplement="http://fasb.org/srt-sup/2022q3">
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<link:roleType roleURI="http://www.zymeworks.com/role/CoverPage" id="CoverPage">
<link:definition>1001 - Document - Cover Page</link:definition>
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<link:usedOn>link:definitionLink</link:usedOn>
<link:usedOn>link:calculationLink</link:usedOn>
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<link:roleType roleURI="http://www.zymeworks.com/role/AuditInformation" id="AuditInformation">
<link:definition>1002 - Document - Audit Information</link:definition>
<link:usedOn>link:presentationLink</link:usedOn>
<link:usedOn>link:definitionLink</link:usedOn>
<link:usedOn>link:calculationLink</link:usedOn>
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<link:linkbaseRef xlink:type="simple" xlink:href="zyme-20221231_pre.xml" xlink:role="http://www.xbrl.org/2003/role/presentationLinkbaseRef" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" />
<link:linkbaseRef xlink:type="simple" xlink:href="zyme-20221231_def.xml" xlink:role="http://www.xbrl.org/2003/role/definitionLinkbaseRef" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" />
<link:linkbaseRef xlink:type="simple" xlink:href="zyme-20221231_lab.xml" xlink:role="http://www.xbrl.org/2003/role/labelLinkbaseRef" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" />
<link:linkbaseRef xlink:type="simple" xlink:href="zyme-20221231_cal.xml" xlink:role="http://www.xbrl.org/2003/role/calculationLinkbaseRef" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" />
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<import namespace="http://www.xbrl.org/2003/instance" schemaLocation="http://www.xbrl.org/2003/xbrl-instance-2003-12-31.xsd" />
<import namespace="http://www.xbrl.org/2003/linkbase" schemaLocation="http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd" />
<import namespace="http://xbrl.org/2005/xbrldt" schemaLocation="http://www.xbrl.org/2005/xbrldt-2005.xsd" />
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<import namespace="http://xbrl.sec.gov/sic/2022" schemaLocation="https://xbrl.sec.gov/sic/2022/sic-2022.xsd" />
<import namespace="http://xbrl.sec.gov/stpr/2022" schemaLocation="https://xbrl.sec.gov/stpr/2022/stpr-2022.xsd" />
<import namespace="http://www.xbrl.org/2009/role/negated" schemaLocation="http://www.xbrl.org/lrr/role/negated-2009-12-16.xsd" />
<import namespace="http://www.xbrl.org/2009/role/net" schemaLocation="http://www.xbrl.org/lrr/role/net-2009-12-16.xsd" />
<import namespace="http://www.xbrl.org/2009/arcrole/fact-explanatoryFact" schemaLocation="http://www.xbrl.org/lrr/arcrole/factExplanatory-2009-12-16.xsd" />
<import namespace="http://xbrl.sec.gov/dei/2022" schemaLocation="https://xbrl.sec.gov/dei/2022/dei-2022.xsd" />
<import namespace="http://fasb.org/us-types/2022" schemaLocation="https://xbrl.fasb.org/us-gaap/2022/elts/us-types-2022.xsd" />
<import namespace="http://fasb.org/srt-types/2022" schemaLocation="https://xbrl.fasb.org/srt/2022/elts/srt-types-2022.xsd" />
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<import namespace="http://www.xbrl.org/dtr/type/2020-01-21" schemaLocation="https://www.xbrl.org/dtr/type/2020-01-21/types.xsd" />
<import namespace="http://fasb.org/us-gaap-sup/2022q3" schemaLocation="https://xbrl.fasb.org/us-gaap/2022q3/us-gaap-sup-2022q3.xsd" />
<import namespace="http://fasb.org/srt-sup/2022q3" schemaLocation="https://xbrl.fasb.org/srt/2022q3/srt-sup-2022q3.xsd" />
<element name="PreferredStockPurchaseRightsMember" type="dtr-types:domainItemType" abstract="true" xbrli:periodType="duration" nillable="true" id="zyme_PreferredStockPurchaseRightsMember" substitutionGroup="xbrli:item" />
<element name="AuditInformationAbstract" type="xbrli:stringItemType" abstract="true" xbrli:periodType="duration" nillable="true" id="zyme_AuditInformationAbstract" substitutionGroup="xbrli:item" />
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