Major depressive disorder (MDD) is a highly prevalent and burdensome condition. This study aims to evaluate the effectiveness, tolerability, and safety of vortioxetine in treating MDD based on real-world data.A systematic search of eight electronic databases was performed from inception until October 2022 to identify real-world studies, excluding randomized controlled trials. We conducted subgroup, meta-regression, sensitivity analyses, publication bias and quality assessments using the random-effects model. The effects were summarized by rates or standardized mean difference (SMD) with 95% confidence intervals (CI).Of the 870 records identified, 11 studies (3139 participants) and 10 case reports or series were eligible for inclusion. Vortioxetine significantly relieved depression symptoms as assessed by both patients (SMD 2.25, 95% CI: 1.60-2.89) and physicians (SMD 3.73, 95% CI: 2.78-4.69). Cognitive function (1.86, 1.11-2.62) and functional disability (1.71, 1.14-2.29) were similarly markedly improved. Subgroup and meta-regression analyses showed that geographic location and medication regimen (whether combined with other antidepressants) were crucial factors influencing the effectiveness, potentially contributing to significant heterogeneity. The estimated response and remission rates were 66.4% (95% CI: 51.2%-81.5%) and 58.0% (48.9%-67.1%), respectively. Vortioxetine was well-tolerated with a pooled dropout rate of 3.5% (1.8%-5.8%), and the most common adverse event was nausea, with an estimated rate of 8.9% (3.8%-15.8%).The study has some limitations, including significant heterogeneity and limited evidence for some outcomes.Vortioxetine is effective, well-tolerated, and safe for treating MDD in clinical practice, with significant improvements observed in depressive severity, cognitive function, and functioning. Future studies should directly compare vortioxetine with other antidepressants in real-world settings to further evaluate its clinical utility.© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.