Relapse following electroconvulsive therapy (ECT) remains a significant clinical challenge despite continuation of pharmacotherapy. We performed a systematic review and meta-analysis (PROSPERO CRD420251000113) of the efficacy and acceptability of continuation ECT (cECT) combined with pharmacotherapy compared to pharmacotherapy alone for relapse prevention following an acute course of ECT for depression. We searched PubMed, Embase, Web of Science, and CENTRAL databases for randomized controlled trials enrolling adults diagnosed with a unipolar or bipolar major depressive episode, who met remission or response criteria after an acute course of ECT and who were subsequently randomized to cECT with pharmacotherapy versus pharmacotherapy alone. The efficacy outcome was the cumulative relapse rate at 6-month follow-up. Data were synthesized using random-effects meta-analyses with effect sizes expressed as relative risks (RRs) with 95% confidence intervals (CIs). Four trials (n = 254) met the inclusion criteria. cECT combined with pharmacotherapy significantly reduced relapse compared to pharmacotherapy alone (RR = 0.57, 95% CI = 0.37–0.88; I2 = 0%; number needed to treat = 7). Sensitivity analyses consistently supported the superiority of cECT under all examined dropout scenarios and analytic approaches. Acceptability, measured by all-cause dropout, was similar between the groups (RR = 1.12; 95% CI = 0.48–2.62; I2 = 0%). cECT combined with pharmacotherapy significantly reduces the RR of relapse by 43% compared to pharmacotherapy alone without compromising acceptability. These findings reinforce the role of cECT as a valuable relapse prevention strategy following successful acute ECT and highlight the need for larger, multicenter trials to further optimize post-ECT prophylaxis.