To conceptualise experiences and perceptions of cancer nurses' potential for occupational exposure when dealing with cytotoxic drugs (CDs). A mixed methods systematic review with framework synthesis. A 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. A 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. The 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. The 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. Joanna Briggs Institute's (JBI) methodology for systematic reviews and framework synthesis indexed studies deductively and inductively. No patient or public contribution. PROSPERO: CRD42022289276.