Multiple observational studies have demonstrated an association with cannabis use and acute myocardial infarction, especially among young adults. However, little is known about the connection with subclinical or electrocardiographic myocardial injury. We hypothesized that cannabis use would be associated with an increased risk of myocardial injury as defined by the cardiac infarction and/or injury score (CIIS). This analysis included 3,634 (age 48.0 ± 5.9 years, 47.1% male, 68.7% Caucasians) participants from the Third National Health and Examination Survey. Cannabis use was defined by self-report. Those with history of cardiovascular disease were excluded. Myocardial injury was defined as electrocardiographic CIIS ≥ 10. Multivariable logistic regression was used to examine the association between cannabis use and myocardial injury. The consistency of this association was tested among subgroups stratified by race, gender, tobacco smoking status, and comorbidities. About 26.0% (n = 900) of participants were ever-cannabis users and 15.5% (n = 538) had myocardial injury. In a model adjusted for potential confounders, ever-cannabis users had 43% increased odds of myocardial injury compared to never users (Odds ratio (95% confidence interval): 1.43 (1.14, 1.80); p = 0.002). This association was stronger among participants with a history of hypertension versus those without (Odds ratio (95% confidence interval): 1.83 (1.36, 2.47) vs 1.17 (0.83, 1.64), respectively; interaction p value 0.04). Cannabis use is associated with an increased risk of myocardial injury among those without cardiovascular disease with effect modification by co-existent hypertension. These novel findings underscore the harmful effects of cannabis use on cardiovascular health and also merit a personalized risk assessment when counseling patients with hypertension on its use.