This study examined 15 post-mortem overdose cases (three females, 12 males; age range 28–78 years, mean 56). Chronic comorbidities included depression, seizure disorder, diabetes, and hypertension. Toxicology revealed lethal or toxic levels of multiple substances, predominantly opioids, antidepressants, ethanol, and benzodiazepines, with 13 cases involving poly substance use. Gross cardiac findings included severe coronary artery disease, dilated cardiomyopathy, and left ventricular hypertrophy, while histology revealed ischemic changes, myocardial infarction, and heart failure. Chronic cardiac pathology was present in 73% of cases, despite only 20% showing conventional cardiovascular risk factors; in decedents under 60, 89% had cardiac pathology versus 33% with risk factors. Findings indicate that substance use, particularly polypharmacy, may contribute to silent cardiac disease, highlighting the need for cardiac screening in substance-using populations.