Importance Mental disorders have been associated with traditional cardiovascular risk factors that may mediate the risk of acute coronary syndrome (ACS). Objective To estimate the association of ACS among patients with mental disorders, as compared with patients without mental disorders. Data Sources MEDLINE, Embase, and PubMed were searched for studies between July 1, 2025, and date of database inception. Study Selection Study screening was performed in duplicates with conflicts resolved upon consensus. Inclusion criteria were as follows: (1) observational or randomized study, (2) measured association with ACS (incident events, risk ratio, odds ratio, hazard ratio [HR]), and (3) investigated any clinical mental disorder (based on DSM and International Classification of Diseases ) before ACS events. Data Extraction and Synthesis This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Data extraction was performed in duplicate and resolved on consensus. Data were quantitatively synthesized through random-effects meta-analysis. The National Institutes of Health Study Quality Assessment Tools were used to assess the quality of included studies. Studies were analyzed from January 1966 to October 2021. Main Outcomes and Measures Association and/or risk of ACS. Results Among 3616 initially identified studies, 25 full-text articles met inclusion criteria with 22 048 504 participants of median (IQR) age 48.0 (34.5-56.1) years, with 13 019 897 males (59.1%). Depressive disorder (HR, 1.40; 95% CI, 1.11-1.78; P = .01; Grading of Recommendations Assessment, Development, and Evaluation [GRADE] certainty = very low), anxiety disorder (HR, 1.63; 95% CI, 1.40-1.89; P &lt; .001; GRADE certainty = low), sleep disorder (HR, 1.60; 95% CI, 1.22-2.10; P &lt; .001; GRADE certainty = low), and posttraumatic stress disorder (PTSD; HR, 2.73; 95% CI, 1.94-3.84; P &lt; .001; GRADE certainty = moderate) were associated with increased risk of ACS. Bipolar (HR, 1.48; 95% CI, 0.47-4.61; P = .28; GRADE certainty = very low) and psychotic (HR, 0.97; 95% CI, 0.01-178.30; P = .06; GRADE certainty = very low) disorders were not significantly associated with increased risk of acute myocardial infarction, although they had similar point estimates to some other mental disorders. Conclusions and Relevance Results of this systematic review and meta-analysis suggest that depressive disorders, anxiety disorders, PTSD, and sleep disorders were associated with an increased risk of ACS. Particularly, PTSD and sleep disorders emerged as significant risk factors for ACS, indicating the potential impact of sleep quality on cardiovascular outcomes. Future research addressing these limitations could provide more nuanced insights into the association between mental health and ACS.