BACKGROUND: Irritable bowel syndrome (IBS) treatment relies on a low level of evidence. In this systematic review with meta-analysis of randomized, double-blind, placebo-controlled trials we assessed the efficacy of antidepressants in IBS. METHODS: This study followed the PRISMA guidelines and was registered in the PROSPERO database (CRD42024502427). PubMed, EMBASE and the Cochrane Library were searched from inception to January 2024. Only randomized, double-blind, placebo-controlled trials were included. Quality of evidence was assessed using the Cochrane tool (RoB 2). A random-effects model was used. Heterogeneity was evaluated by the statistic and publication bias by funnel plots and the Egger test. RESULTS: The search strategy identified 1340 studies, of which 20 were included in the systematic review and 16 in the meta-analysis, totaling 1428 patients. The meta-analysis unveiled the efficacy of antidepressants in patients with IBS in overall symptom improvement (odds ratio [OR] 3.02; 95% confidence interval [CI] 2.16-4.2). Subgroup analysis revealed similar results regarding the efficacy of tricyclic antidepressants (OR 3.39, 95%CI 2.24-5.12); of selective serotonin reuptake inhibitors (OR 2.39, 95%CI 1.14-5.01); in patients refractory to first-line measures (OR 2.96, 95%CI 1.67-5.25); in patients without known comorbid psychological conditions (OR 2.92, 95%CI 1.6-5.31); and in the improvement in abdominal pain (OR 3.27, 95%CI 1.63-6.53), and bloating (OR 2.4, 95%CI 1.11-5.22). Publication bias was detected, and potential sources were identified. Sub-analysis without these sources of bias revealed similar results. CONCLUSIONS: Antidepressants demonstrate efficacy in IBS. These medications can be beneficial to patients resistant to initial treatments and those lacking psychopathological symptoms.