Background <p>Polypharmacy (PP) is a rising clinical challenge among patients with a cancer diagnosis. Uncertainty remains regarding its exact burden, exact prevalence estimates, and definitional themes in this vulnerable cohort of patients.</p> Methods <p>We searched PubMed, EMBASE, Scopus, the Cochrane Database of Systematic Reviews (CDSR), and Google Scholar, for studies published between 2000 and 2025 for eligible studies reporting on polypharmacy in cancer patients. These were critically appraised for eligibility and inclusion by two independent reviewers. Using quality and random effect models, pooled estimates of the prevalence of PP, prevalence by type of cancer, and geographical spread were determined. The prevalence rates of potentially inappropriate medications (PIMs) and drug-drug interactions (DDIs) were also estimated. Heterogeneity among the included studies was reported by corresponding <i>I</i>² estimates.</p> Results <p>This meta-analytical review involved 20 studies comprising (<i>n</i> = 102,100) participants. The overall pooled prevalence of polypharmacy among patients with cancer was 29% (95% CI 10–52%) using the quality effects model, and 58% (95% CI 50–62%) using the random effects model. The overall heterogeneity among the included studies was significant (<i>I</i>² = 100%, <i>p</i> &lt; 0.001) for the random effects models.</p> Conclusion <p>From this meta-analysis of studies with diverse designs, we found a high pooled prevalence of polypharmacy among patient cohorts with cancer, with marked variability across studies. Given this level of heterogeneity, future prospective and systematic studies are needed to better characterize the determinants and consequences of polypharmacy to guide strategies that may improve patient outcomes in these cohorts.</p> Systematic review registration <p>PROSPERO, Number CRD42024576772.</p>