OBJECTIVES: To evaluate whether osteopathic and related manual interventions improve adult mental health (depression, anxiety, stress) and psychophysiological measures (eg, heart rate variability, skin conductance). DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: PubMed, MEDLINE (Ovid), Scopus, Cochrane, and AMED, searched through September 2024. ELIGIBILITY CRITERIA: English-language RCTs with ≥30 participants investigating osteopathic or related manual therapies (eg, myofascial release, high-velocity low-amplitude thrusts) delivered by qualified practitioners, compared with no treatment or sham, and reporting immediate postintervention mental health or psychophysiological outcomes. DATA EXTRACTION AND SYNTHESIS: Full-text screening, risk-of-bias assessment and data extraction were conducted independently by multiple reviewers using a standardised Joanna Briggs Institute (JBI) Extraction Form. Risk of bias was assessed using the JBI Critical Appraisal Checklist. For meta-analyses, Hedges' RESULTS: 20 RCTs were included. Osteopathic interventions reduced depression (Hedges' CONCLUSIONS: Osteopathic and related manual therapies may reduce depression and influence certain psychophysiological markers, particularly in pain populations, but uncertainty and heterogeneity limit confidence. More rigorous, larger, and longitudinal RCTs are needed. TRIAL REGISTRATION NUMBER: This meta-analysis was not formally registered, though the protocol and search strategy can be found at Open Science Framework, registration identification: https://osf.io/jrtpx/.