BACKGROUND: Due to the unsatisfactory therapeutic effects of current antidepressants, research has been launched into alternative treatment approaches, such as the administration of psychedelics. Psilocybin, a classic hallucinogen, has been shown to exert considerable positive influence on depression symptoms through its serotonergic and glutamatergic effects. This systematic review and meta-analysis aimed to evaluate the effectiveness of psilocybin in treating depression. METHODS: A comprehensive search of Medline (via PubMed) and the Cochrane Library databases was conducted to identify relevant studies. Inclusion criteria were applied to select studies that investigated the therapeutic impact of psilocybin on depression. A mixed-effects multi-level model was used to estimate the overall effect size. Effectiveness over time was also investigated as a secondary analysis. RESULTS: The results of the primary analysis revealed a large and clinically observable reduction (SMC: -1.24, 95%CI: -1.83 to -0.65, I2level2 = 11.39%, I2level3 = 77.67%) of depressive symptomatology in patients receiving psilocybin in addition to supportive therapy compared to baseline measurements. The decrease was also marked when compared to placebo (p-value = 0.032). The results remained significant even when a secondary analysis assessed the effect in various time intervals since the administration of psilocybin. CONCLUSION: This systematic review and meta-analysis substantiate the claim that psilocybin is superior in treating depression compared to established psychotherapy alone used for treating depression. This finding warrants further studies with larger sample sizes and across a longer timeframe.