Background <p>Individuals with severe mental illness (SMI) are frequently prescribed both antipsychotic medications and cardiometabolic medications, placing them at increased risk of drug-drug interactions (DDIs). However, evidence guiding the identification and management of these interactions remains fragmented. To address this research gap, in this study, we systematically summarize potential DDIs between antipsychotic and cardiometabolic medications and evaluate the performance of commonly used online DDI checkers in identifying these interactions.</p> Methods <p>A systematic review was conducted using PubMed, Embase, PsycINFO, and Web of Science to identify studies reporting DDIs between antipsychotic and cardiometabolic medications up to March 20, 2024. Disproportionality analysis was performed using data from the Canada Vigilance Adverse Reaction Online Database (1965–2024) and the FDA Adverse Event Reporting System (FAERS, 2004–2024) to identify DDI signals. Four online DDI checkers—Drugs.com, Medscape, ddinter, and ANSM Thesaurus—were used to evaluate their ability to identify the observed interactions.</p> Results <p>Across all sources, 1776 unique potential DDIs were identified. Clozapine was the most frequently implicated antipsychotic medication in a systematic review, often associated with musculoskeletal and connective tissue disorders. DDI signals associated with aripiprazole and quetiapine were also frequently observed. Except for nervous system disorders and cardiometabolic disorders, the adverse outcomes of DDIs involving aripiprazole or quetiapine were most commonly associated with musculoskeletal and connective tissue disorders and gastrointestinal disorders. Quetiapine interactions, especially with lipid-lowering agents such as simvastatin, were also commonly linked to musculoskeletal and connective tissue disorders. Notably, 45.4% of identified DDIs were not flagged by any of the four DDI checkers. Drugs.com detected the most interactions. Combinations of clozapine and metformin, ziprasidone and metformin, and risperidone and clonidine were consistently identified by at least three of the checkers.</p> Conclusions <p>This systematic review and disproportionality analysis identified potential DDIs between antipsychotic medications and cardiometabolic medications, many of which were not captured by commonly used DDI checkers. These findings underscore the need for clinicians to consult multiple sources and apply clinical judgment when prescribing these medications. Improved integration of pharmacovigilance data into DDI checkers may enhance the identification and prevention of harmful interactions.</p>