Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.