Abstract Context Zinc is an essential trace mineral required for the function of brain and neural structures. The role of zinc supplementation in the prevention and treatment of depression has been suggested in clinical studies that reported a reduction in depressive symptoms. Objective The aim of this review was to determine whether zinc supplementation vs placebo can prevent or improve depressive symptoms in children, adolescents, or adults. Data Sources Five electronic databases were searched, and studies published until September 2019 were included without language restriction. Study Selection Randomized, controlled, crossover trials that evaluated the effect of zinc supplementation vs a comparator for prevention or improvement of depressive symptoms in children, adolescents, or adults were eligible for inclusion. Data Extraction Two authors independently performed data extraction and risk-of-bias assessment. Results The initial search identified 12 322 studies, 5 of which were eligible for meta-analysis. The standardized mean difference (SMD) showed an average reduction of 0.36 point (95%CI, −0.67 to −0.04) in the intervention group compared with the placebo group. Forstudies in which the mean age of participants was ≥ 40 years, the SMD was reduced by 0.61 point (95%CI, −1.12 to −0.09) in the intervention group vs the placebo group. The meta-analysis by sample size (< 60 individuals and ≥ 60 individuals) did not show an effect of zinc supplementation in reducing depressive symptoms (SMD −0.28; 95%CI, −0.67 to −0.10; and SMD −0.52; 95%CI, −1.10 to 0.06). Conclusion Zinc supplementation may reduce depressive symptoms in individuals treated with antidepressant drugs for clinical depression. Systematic Review Registration PROSPERO registration number CRD42018081691.