Objective <p>Gastrointestinal adverse effects are the most commonly reported adverse effects associated with the use of antidepressants. While existing studies on the gastrointestinal effects of antidepressant medications offer valuable insights, there are still opportunities to enhance the evidence base.</p> Methods <p>We included double-blind randomized controlled trials of major depressive disorder (MDD). Eligible studies must focus on comparing the use of 21 commonly used antidepressants in patients with MDD and reporting data on treatment-emergent gastrointestinal SEs. We selected 196 studies that reported specific numbers of individuals with gastrointestinal adverse effects, involving a total of 57,162 patients. A network and dose‒response meta-analysis was conducted.</p> Results <p>Compared with placebo, 16 antidepressants had higher odds ratios (ORs) for nausea and vomiting, 15 antidepressants had higher ORs for constipation, 8 antidepressants had higher ORs for diarrhoea, 8 antidepressants had higher ORs for anorexia, 12 antidepressants had higher ORs for dry mouth, and 3 antidepressants had higher ORs for dyspepsia.</p> Conclusions <p>Commonly used antidepressants have different gastrointestinal effects. Duloxetine, levomilnacipran, and vilazodone carry a higher risk of inducing nausea and vomiting, whereas trazodone, amitriptyline, agomelatine, and mirtazapine tend to be better tolerated. Amitriptyline, clomipramine, and reboxetine are more prone to induce constipation. Diarrhoea is more commonly associated with vilazodone, fluvoxamine, and sertraline. Amitriptyline, reboxetine, and duloxetine are more likely to cause anorexia. Amitriptyline, reboxetine, and trazodone are related to causing dry mouth. Compared with the placebo, amitriptyline, fluoxetine, and paroxetine were associated with a greater incidence of dyspepsia.</p>