This study aimed to evaluate the efficacy and safety of lumateperone in treating bipolar disorder and schizophrenia. A comprehensive literature search was conducted across multiple databases and websites from inception to July 16, 2024, to identify both published and unpublished randomized controlled trials (RCTs). Meta-analyses were performed using random-effects or fixed-effects models depending on statistical heterogeneity. Relative risks (RRs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to summarize the effects. Out of 931 records screened, 7 RCTs (four focusing on bipolar depression and 3 on schizophrenia) were eligible for inclusion. Lumateperone was efficacious in reducing depressive symptoms in bipolar depression (SMDs = -0.36, 95% CI: -.59 to -.13). In treating schizophrenia, lumateperone exhibited a lower combined SMD of -0.14 (95% CI: -.27 to 0, P = .051, I-2 = 49.6%), showing no significant difference from the placebo group, although the P-value approached significance. The lumateperone group showed significantly higher response rates compared with placebo in both bipolar depression (RRs = 1.27, 95% CI = 1.07 to 1.51) and schizophrenia (RRs = 1.44, 95% CI = 1.12 to 1.86). Common treatment-emergent adverse events included somnolence, dry mouth, dizziness, nausea, and headache (RRs = 1.30 to 3.29). Importantly, lumateperone did not significantly increase extrapyramidal symptoms (EPS, RRs = 1.46, 95% CI = .84 to 2.53). Lumateperone is effective in treating bipolar depression but does not significantly reduce symptom severity in schizophrenia. It has a favorable safety and tolerability profile. However, caution is warranted in interpreting these findings due to the limited number of studies included.<br />