ST-segment elevation myocardial infarction (STEMI) in patients with concomitant multivessel coronary artery disease is associated with poor prognosis. We sought to determine the merits of percutaneous coronary intervention of the culprit-only revascularization (COR) compared with multivessel revascularization (MVR) approach. Multiple databases were queried to identify relevant articles. Data were analyzed using a random-effect model to calculate unadjusted odds ratio (OR) and relative risk. A total of 28 studies comprising 26,892 patients, 18,377 in the COR and 8,515 in the MVR group were included. The mean age of patients was 63 years, comprising 72% of male patients. The baseline characteristics of the 2 treatment groups were comparable. On a median follow-up of 1-year, COR was associated with a significantly higher odds of major adverse cardiovascular events (MACE; OR 1.36, 95% confidence interval [CI] 1.10 to 1.70, p = 0.005), angina (OR 2.28, 95% CI 1.83 to 2.85, p ≤ 0.00001) and revascularization (OR 1.76, 95% CI 1.22 to 2.54, p = 0.002) compared with patients undergoing MVR for STEMI. The all-cause mortality (OR 1.18, 95% CI 0.91 to 1.53, p = 0.22), cardiovascular mortality (OR 1.30, 95% CI 0.98 to 1.72, p = 0.07), rate of heart failure (OR 1.17, 95% CI 0.86 to 1.59, p = 0.31), need for coronary artery bypass graft (CABG) (OR 1.47, 95% CI 0.82 to 2.64, p = 0.19), repeat myocardial infarction (MI) events (OR 1.23, 95% CI 0.93 to 1.64, p = 0.15) and risk of stroke (OR 1.27 95% CI 0.68 to 2.34, p = 0.45%) were similar between the two groups. A subgroup analysis based on follow-up duration and study design mostly followed the results of the pooled analysis except that the risk of repeat MI events were significantly lower in the MVR group across RCTs (OR 1.46, 95% CI 1.10 to 1.94, p = 0.009). In contrast to the culprit-only approach, MVR in patients with STEMI is associated with a significant reduction in MACE, angina and need for revascularization.