Inflammatory processes are involved in chronic diseases. It has been suggested that melatonin reduces inflammation by its radical scavenging properties; however, the results of the previous studies are inconclusive. The objective of the present meta-analysis is to determine the direction and magnitude of melatonin supplementation effect on inflammatory biomarkers.Databases including PubMed, Scopus, Cochran Library, Embase, and Google Scholar were searched up to April 2019. Meta-analysis was performed using random-effect model. Subgroup analysis, sensitivity analysis, and meta-regression were also carried out.Thirteen eligible studies with 22 datasets with total sample size of 749 participants were included in the meta-analysis. Melatonin supplementation significantly decreased TNF-α and IL-6 levels [(WMD = - 2.24 pg/ml; 95% CI - 3.45, - 1.03; P < 0.001; I2 = 96.7%, Pheterogeneity < 0.001) and (WMD = - 30.25 pg/ml; 95% CI - 41.45, - 19.06; P < 0.001, I2 = 99.0%; Pheterogeneity < 0.001)], respectively. The effect of melatonin on CRP levels was marginal (WMD = - 0.45 mg/L; 95% CI - 0.94, 0.03; P = 0.06; I2 = 96.6%, Pheterogeneity < 0.001).The results of the present meta-analysis support that melatonin supplementation could be effective on ameliorating of inflammatory mediators.