Background: Adjunctive ketamine with electroconvulsive therapy (ECT) has been investigated for treating major depressive disorder (MDD), but the findings have been inconsistent. Aim: This is an updated meta-analysis of the efficacy and safety of ketamine augmentation of ECT in the treatment of MDD. Methods: Randomized controlled trials (RCTs) reporting on the efficacy and safety of ketamine and ECT were identified and analyzed. Results: Seventeen RCTs (n = 1,035) compared ketamine alone or ketamine plus other anesthetic drugs (n = 557) with other anesthetic agents (n = 478) in MDD patients who received ECT. Ketamine+other anesthetic drugs was superior in improving depressive symptoms over other anesthetic medications at early study time point, but not at post-ECT or end of study time points. Ketamine alone was not more efficacious in treating depressive symptoms than other anesthetic drugs at early study, post-ECT and end of study time points. Sensitivity analysis and 19 of the 20 subgroup analyses also confirmed the lack of significance of these findings. Eleven RCTs testing the effects of ketamine on neurocognitive functions with various test batteries found mixed results. Ketamine alone significantly increased blood pressure more than other anesthetic drugs in MDD treated with ECT. Conclusion: Compared to other anesthetic agents, ketamine alone does not appear to improve the efficacy of ECT. However, ketamine+other anesthetic combinations may confer a short-term advantage in improving depressive symptom at the early stages of ECT.