Aims: Polypharmacy is associated with multiple adverse health outcomes. The objective of this systematic review and meta-analysis was to explore the association between polypharmacy and depression. Methods and results: A systematic literature review was conducted by searching MEDLINE, Scopus, Science Direct, and CINAHL Complete to identify studies assessing the association between polypharmacy and depression published until November 2020. A meta-analysis was performed using random effect models. Heterogeneity was assessed using the I 2 -statistic. Nineteen studies were included in the meta-analysis. We found that an increase in the number of drugs was associated with an increased risk of depression (OR = 1.55 [95% CI: 1.01, 2.36; I 2 = 62%, n = 2]). Further, polypharmacy defined as the concurrent use of five or more medications was associated with an increased risk of depression (OR = 1.73 [95% CI: 1.39, 2.14], I 2 = 83%, n = 8). Conclusion: This meta-analysis revealed that polypharmacy, both discretely and categorically defined, was associated with an increased risk of depression.