Background/Objective <p>Substance abuse poses a significant public health issue in many nations across the globe. This study investigates the impact of opium consumption on rehospitalization and mortality in patients with ST-elevation myocardial infarction (STEMI) over a 2-year period.</p> Methods <p>This cross-sectional study was conducted at Chamran Tertiary Heart Center and investigated the impacts of opium use on survivors of STEMI during the COVID-19 pandemic (2021–2023). Two years after their myocardial infarction, eligible patients were invited for a follow-up appointment with a blinded cardiologist. During this visit, data were collected on medical history, comorbidities, results of coronary angiography and interventions, current opium dependency, rehospitalization, and mortality. Data analysis was performed using IBM SPSS Statistics version 25.</p> Results <p>Out of 219 patients, the mean age of the opium-using group was 53.94 ± 10.55 years, while the non-opium users had an average age of 56.30 ± 11.66 years. Comorbidities were not significantly different between the two groups. Among the participants, 48 required hospitalization, including eight individuals (21.6%) from the opium group and 40 patients (22.1%) in the non-opium-using group, primarily for heart failure or recurrent percutaneous coronary intervention. Additionally, 35 patients died, predominantly due to cardiogenic shock.</p> Conclusions <p>This study found no significant difference in comorbidity burden, stenosis location, rates of rehospitalization, or mortality between opium users and non-users in patients diagnosed with STEMI over 2 years. Future research with larger sample sizes is needed to explore these associations in greater depth.</p>