To investigate the efficacy and safety of saffron in the treatment of major depressive disorder (MDD) in comparison to placebo and synthetic antidepressants.We conducted a systematic search in several electronic databases as well as manual search in bibliographies of relevant studies. We included randomized controlled trials that investigated the efficacy and safety of saffron for treating MDD in adults in comparison to either placebo or synthetic antidepressants. Primary outcome was change in scores on depressive symptoms from baseline. Secondary outcomes included remission rate, response rate, and drop-out rate for all reasons. We chose a random-effects model in order to obtain more conservative results. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated as the overall effect index by inverse variance models.Seven studies were included in this meta-analysis. Overall quality of these included studies was moderate. As for the primary outcome, saffron showed more improvements in depression symptoms when compared with placebo, with an SMD of -1.22 (95% CI -1.94, -0.49, =0.001). Meanwhile, saffron was as effective as synthetic antidepressants, with an SMD of 0.16 (95% CI -0.25, 0.57, =0.44). Moderate heterogeneity existed in our analysis. Through subgroup analyses, we found that treatment dosage and duration, types of synthetic antidepressants administered in the comparison group, and outcome measures could explain most of the variance. No differences were found in remission rate, response rate, or drop-out rate.Saffron was effective in the treatment of MDD and had comparable efficacy to synthetic antidepressants. Saffron was also a safe drug without serious adverse events reported.