AimTo conceptualise experiences and perceptions of cancer nurses' potential for occupational exposure when dealing with cytotoxic drugs (CDs).DesignA mixed methods systematic review with framework synthesis.Methods and Data SourcesA literature search was conducted in February 2022 in CINAHL PubMed, Web of Science, Ovid Nursing, and PsycINFO, and it was reported using the PRISMA guidance.ResultsA synthesis of 38 studies revealed new categories of perceived solutions, side effects, and risky behaviour as well as three levels of experience and perception: individual, shared, and cultural, rather than the a priori theory.ConclusionsThe review conclude that individuals espouse safe handling and administration of CDs. Synthesis highlights a complex interplay between self‐reported perception and the observed experience of potential occupational exposure to cytotoxic drugs.Implications for Professional PracticeThe framework synthesis highlights the difference between the perception of espoused practice and the experience of practice. Observation and risk assessment must be used to enhance safe practice. Organisations must take seriously the perception and experience of the adverse effects of administering cytotoxic drugs to support cancer nurses.Reporting MethodJoanna Briggs Institute's (JBI) methodology for systematic reviews and framework synthesis indexed studies deductively and inductively.No patient or public contribution.Trial RegistrationPROSPERO: CRD42022289276