Prompt identification of acute coronary syndrome is a challenge in clinical practice. The 12-lead electrocardiogram (ECG) is readily available during initial patient evaluation, but current rule-based interpretation approaches lack sufficient accuracy. Here we report machine learning-based methods for the prediction of underlying acute myocardial ischemia in patients with chest pain. Using 554 temporal-spatial features of the 12-lead ECG, we train and test multiple classifiers on two independent prospective patient cohorts (n = 1244). While maintaining higher negative predictive value, our final fusion model achieves 52% gain in sensitivity compared to commercial interpretation software and 37% gain in sensitivity compared to experienced clinicians. Such an ultra-early, ECG-based clinical decision support tool, when combined with the judgment of trained emergency personnel, would help to improve clinical outcomes and reduce unnecessary costs in patients with chest pain.