To assess the efficacy and acceptability of antidepressants in adults with ischemic heart disease (IHD). We gathered all available randomized-controlled trials comparing antidepressants versus placebo or other antidepressants in adults with IHD. The primary outcome was depressive symptoms at the study endpoint, as measured by validated rating scales. We pooled data in a meta-analysis using a random-effects model. The confidence in the estimates (or certainty of the evidence) was assessed using the GRADE approach. Antidepressants appeared to be more effective than placebo in reducing depressive symptoms (11 comparisons; 1685 participants; standardized mean difference -0.71, 95% confidence interval: -1.11 to -0.30; GRADE quality: moderate). This result was confirmed in the subgroup of serotonin selective reuptake inhibitors, and for the single drugs sertraline and citalopram, with a greater magnitude of effect and a higher quality of evidence for the former. No differences between antidepressants and placebo emerged in terms of acceptability and tolerability, quality of life, mortality, and cardiovascular events. Only two small head-to-head studies were identified. Sertraline is a reasonable first-line choice in patients with IHD and depression, whereas the role of citalopram as the first-line agent should be reconsidered.