BACKGROUND: The study aimed to comprehensively analyze and establish a framework for evaluating the efficacy of microbiome-targeted treatment (MTT) for depression. METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and the Chinese National Knowledge Infrastructure database for randomized controlled trials (RCTs) on MTT in treating depression until October 19, 2023. A meta-analysis was conducted to evaluate the efficacy and safety of MTT. Comprehensive subgroup analyses were undertaken to explore factors influencing MTT's efficacy in treating depression. This study was registered with PROSPERO (CRD42023483649). RESULTS: The study selection process identified 51,570 studies, of which 34 met the inclusion criteria. The overall pooled estimates showed that MTT significantly improved depression symptoms (SMD -0.26, 95% CI [-0.32, -0.19], I CONCLUSIONS: Despite the overall effectiveness of MTT in treating depression and its acceptable safety profile, caution is warranted in drawing this conclusion due to limitations posed by the small sample size of included studies and heterogeneity. The efficacy of MTT for depression exhibits variation influenced by geography, patient comorbidities, and duration of administration.