BACKGROUND: Cancer therapy de-escalation aims to reduce treatment intensity, minimizing the burden of short- and long-term toxicities on patients and family caregivers while maintaining current survival rates. While this approach holds potential benefits, it comes at a risk of worse patient health outcomes or treatment failure. An understanding of patient and family caregiver perspectives regarding cancer therapy de-escalation is required to design successful patient-and-caregiver-informed clinical trials, and optimally provide related patient-centered care. AIM: To identify and synthesize the literature about patient and family caregiver perspectives of cancer therapy de-escalation to guide clinical care, research, decision-support resources, and education. METHODS: Following the Joanna Briggs Institute methodology, a systematic literature search was conducted in MEDLINE, EMBASE, PsycINFO, and CINAHL. We included quantitative, qualitative, and mixed-methods studies involving patients of all ages and cancer diagnoses and their family caregivers that focused on perceptions of cancer therapy de-escalation. Extracted data were organized according to the Framework for De-implementation in Cancer Care Delivery. Study quality was appraised. RESULTS: Twenty studies were included. De-escalation perspectives varied between patients and family caregivers, with factors including clinician trust and desire to improve quality of life noted as influential in de-escalation decisions. The decision-making process could be better supported through the provision of timely patient and family caregiver information and clinician communication training. CONCLUSION: Cancer therapy de-escalation decisions are complex and multifactorial. Future research exploring which factors influence patient and family decision-making may offer insight into the design of optimal informational and supportive interventions.