PURPOSE: The aim of this comprehensive systematic review and meta-analysis was to evaluate the beneficial effects of melatonin supplementation on brain-derived neurotrophic factor (BDNF) concentration and clinical depressive disorder. METHODS: A comprehensive electronic search was conducted of Medlin, Web of Science, Science Direct, and Google scholar, from database inception to January 20, 2021. Studies were eligible if they: (1) were a clinical trial; (2) enrolled adults; (3) assessed the effect of melatonin supplementation on serum concentration of BDNF or depression score. Overall effects, as weighted mean difference (WMD), were calculated for concentration of BDNF and depression score. RESULTS: Melatonin supplementation yielded no significant effect on BDNF concentration (WMD: -5.61; 95% CI: -14.10, 2.88; I-square: 85.6%), but improved depression by decreasing the score (WMD: -0.76; 95% CI: -1.12, -0.4; I-square: 88.0%). Due to high heterogeneity between studies, subgroup analysis for gender, duration and dose in BDNF studies and duration, age, dose, continent and Questionnaire type in depression studies, was utilised. The subgroup analysis showed that melatonin supplementation had a significant decreasing effect on BDNF levels in doses ≤ 10 mg/day, with more than 4 weeks of duration, and in men. CONCLUSION: The present study revealed that melatonin supplementation has a decreasing effect on depression in all duration of studies and doses subgroup and in age more than 65 years in depression studies but heterogenicity of the included studies, did not allow a definitive conclusion. There is limited evidence for effects of melatonin on serum BDNF. IMPLICATIONS FOR PRACTICE: Melatonin is a safe and effective supplement for depressive patients.