Introduction: Acute coronary syndrome (ACS) is a common, sometimes difficult to diagnose spectrum of diseases. Given the diagnostic challenge, it is sensible for emergency physicians to have an approach to prognosticate patients with possible ACS. The objective of this review was to investigate the ability of the HEART score to predict major adverse cardiac events (MACE) in patients presenting to the ED with possible ACS. Methods: Eleven databases and other sources identified 468 potentially relevant studies. Sixty-seven studies underwent full text review with 25 studies meeting eligibility criteria. Main outcome measures were pooled prevalence, risk ratio (RR), and absolute risk reduction (ARR) for MACE within six weeks of ED evaluation, comparing HEART score 0–3 versus 4–10. Model discrimination (sensitivity, specificity, concordance statistic) and calibration (observed to expected events ratio) were also evaluated. Results: Data from 25 studies including 41,397 patients were combined in the meta-analysis. In total, 4815 patients (11.6%) developed MACE. Among 18,866 patients with HEART score 0–3, 396 (2.1%) developed MACE (RR 0.08; ARR 0.20). Outcome measures were consistent across planned subgroup and sensitivity analyses. Among studies with secondary outcome data for patients with HEART score 0–3, 5 of 6461 (0.1%) died and 75 of 7556 (1.0%) had a myocardial infarction. Conclusion: The HEART score provides a reliable quantitative risk assessment of MACE in ED patients with possible ACS. Emergency clinicians should consider using the HEART score to facilitate risk communication and shared decision making with patients and other care providers.