Background: Early myocardial reperfusion therapy (< 12 h) in patients with acute myocardial infarction (AMI) can significantly improve their prognosis. However, the effect of late reperfusion (> 12 h) remains controversial. In this study, the effects of late reperfusion versus standard drug therapy on the outcomes of patients with AMI were evaluated by systematic review and meta-analysis. Methods: PubMed, Embase, Medline, Cochrane, Wanfang, and CNKI databases were searched for eligible studies for the present study. Meta-analysis was performed using RevMan 5.3.3 software. Relative risk (RR) and the 95% confidence interval (CI) were used to compare the outcomes between the two groups. The main outcome measures were major adverse cardiac events (MACEs), all-cause mortality, recurrent myocardial infarction (MI), and heart failure. Results: Eighteen studies were identified including 14,677 patients, of whom 5157 received late reperfusion with percutaneous coronary intervention (PCI) and 9520 received medication therapy (MT). Compared to MT, late PCI was associated with decreased all-cause mortality (RR 0.60, 95% CI 0.44-0.83; p = 0.002), MACEs (RR 0.67; 95% CI 0.50-0.89; p < 0.001), and heart failure (RR 0.76; 95% CI 0.60-0.97; p = 0.03), while there was also a trend toward decreased recurrent MI (RR 0.70; 95% CI 0.47-1.05; p = 0.08). However, subgroup analysis according to time to PCI showed that the clinical benefit was only from PCI after 12 h but not from 2 to 60 days of the onset of symptoms. Conclusions: The present meta-analysis suggested that PCI performed > 12 h but not 2-60 days after AMI is associated with significant improvement in clinical outcomes. However, these results need further rigorously designed large sample size clinical trials to be validated.