Background Methamphetamine‐associated acute coronary syndrome (ACS) has not been previously well studied. Methods This retrospective, single‐center study included all patients aged 18 to 65 years who presented with ACS and underwent coronary angiography from 2012 to 2022. Patients who used cocaine or had other non‐type 1 myocardial infarction were excluded. Cox proportional hazard regression and survival analyses were performed to assess all‐cause mortality. Results One hundred ninety‐four patients with methamphetamine‐associated ACS were identified from 1309 ACS cases, for a prevalence of 14.8%. When compared with the 1115 patients with ACS without methamphetamine use, patients with methamphetamine‐associated ACS were mostly younger men with a median age of 52 years (Q1–Q3: 47–57) versus 57 years (Q1–Q3: 51–61, P <0.001). More patients with methamphetamine‐associated ACS were found to have nonobstructive coronary diseases (24.2% versus 10.6%, P <0.001). Despite being younger and having a lower burden of traditional risk factors, patients with methamphetamine‐associated ACS experienced significantly lower survival (log‐rank test, P =0.005), a pattern that persisted after adjustment for confounders. In multivariable Cox regression, methamphetamine use emerged as the strongest independent predictor of all‐cause mortality, with an adjusted hazard ratio of 2.08 (95% CI, 1.40–3.09; P <0.001). Conclusions ACS related to methamphetamine use is primarily observed in younger men with adverse social determinants of health and is strongly associated with mortality. Strategies for prevention unique to this population are warranted.