This study aimed to evaluate the risk of various substances in young acute myocardial infarction (AMI) inpatients and analyze patient demographics and hospital outcomes for significant substance use risk factors. We conducted a retrospective analysis of the Nationwide Inpatient Sample data (2010–2014). Patients (aged 15–22 years) with a primary diagnosis for AMI (N = 1,694) were compared with non-AMI (N = 9,465,255) inpatients for odds ratio (OR) of substance use by logistic regression model, adjusted for demographics, medical risk factors, and comorbid substance use. Tobacco (28.4%) and cannabis (14.9%) use were most prevalent in AMI inpatients. Cocaine (OR = 3.9), amphetamine (OR = 2.3), and cannabis (OR = 1.3) users were at higher risk of AMI hospitalizations. Higher proportion of cannabis users (14.7%) had major severity of illness at admission and higher mean total charge ($53,608) compared with that seen in cocaine and amphetamine users. Angioplasty was used more in cannabis users (19.4%) than others. The in-hospital mortalities were 2.7% and 2% in overall AMI cohort and cannabis users, respectively, and none in cocaine and amphetamine users. Our study demonstrates a higher prevalence and significant odds of AMI inpatients with cannabis use, along with the potential cost burdens because of severe morbidity and higher use of treatment modalities. Physicians need to familiarize themselves with rising use of cannabis and other substances in adolescent and younger population and the typical presentations of cannabis-induced myocardial infarction.