BACKGROUND: Lurasidone is a second-generation antipsychotic with antidepressant properties, but its effect on depressive symptoms across diagnostic domains is not known. AIMS: This systematic review aims to synthesise the evidence for the transdiagnostic efficacy of lurasidone in reducing depressive symptoms. METHOD: Electronic databases were searched up to October 2024 to identify randomised controlled trials comparing the effects of lurasidone and placebo on depressive symptoms, as measured by any standardised scale, in populations with different psychiatric diagnoses. Acceptability, tolerability and safety were also measured. The Cochrane risk of bias tool was used to assess study quality, and the GRADE tool to evaluate certainty of evidence. A random-effects meta-analysis was performed to estimate standardised mean differences (SMDs, for continuous outcomes) or relative risks (for dichotomous outcomes) with 95% CI. RESULTS: Fourteen trials met inclusion criteria. Pooled analysis of 5239 participants found lurasidone to be more efficacious than placebo in improving depression scores (SMD -0.26, 95% CI -0.37, -0.15) across multiple diagnoses (including schizophrenia, bipolar disorder and major depressive disorder). Secondary analyses showed better acceptability (relative risk 0.55, 95% CI 0.43, 0.71) and safety (relative risk 0.73, 95% CI 0.58, 0.91) and comparable tolerability (relative risk 0.74, 95% CI 0.54, 1.02) between lurasidone and placebo. The main limitations were the high risk of bias of several included studies and the high heterogeneity observed in our findings. CONCLUSION: Lurasidone is a potentially efficacious and safe strategy for reducing depressive symptomatology across a range of psychiatric diagnoses. Further long-term, robust trials employing precision psychiatry methods are needed to support its broader use to target depressive symptoms transdiagnostically.