BACKGROUND AND AIMS: The importance of risk stratification in patients with chest pain extends beyond diagnosis and immediate treatment. This study sought to evaluate the prognostic value of electrocardiogram feature-based machine learning models to risk-stratify all-cause mortality in those with chest pain. METHODS: This was a prospective observational cohort study of consecutive, non-traumatic patients with chest pain. All-cause death was ascertained from multiple sources, including the CDC National Death Index registry. Six machine learning models were trained for survival analysis using 73 morphological electrocardiogram features (80% training with 10-fold cross-validation and 20% testing), followed by a variational Bayesian Gaussian mixture model to define distinct risk groups. The resulting classification performance was compared against the HEART score. RESULTS: The derivation cohort included 4015 patients (age 59 ± 16 years, 47% women). The mortality rate was 20.3% after a median follow-up period of 3.05 years (interquartile range 1.75-5.32). Extra Survival Trees outperformed other forecasting models, and the derived risk groups successfully classified patients into low-, moderate-, and high-risk groups (log-rank test statistic = 121.14, P < .001). This model outperformed the HEART score, reducing the rate of missed events by >90% with a negative predictive value and sensitivity of 93.4% and 85.9%, compared to 89.0% and 75.0%, respectively. In an independent external testing cohort (N = 3095, age 59 ± 15 years, 44% women, 30-day mortality 3.5%), patients in the moderate [odds ratio 3.62 (1.35-9.74)] and high [odds ratio 6.12 (2.38-15.75)] risk groups had significantly higher odds of mortality compared to those in the low-risk group. CONCLUSIONS: The externally validated machine learning-based model, exclusively utilizing features from the 12-lead electrocardiogram, outperformed the HEART score in stratifying the mortality risk of patients with acute chest pain. This may have the potential to impact the precision of care delivery and the allocation of resources to those at highest risk of adverse events.