The efficacy and safety of novel oral P2Y12 receptor inhibitors (prasugrel and ticagrelor) are subjects of contention in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI, and the optimal duration of therapy remains uncertain. We searched PubMed, Embase, Cochrane Library, CNKI, VIP, and WanFang Data to identify randomized controlled trials comparing novel oral P2Y12 receptor inhibitors with clopidogrel in patients with STEMI undergoing PCI until February 2016. The primary efficacy and safety endpoint were all-cause mortality and major/minor bleeding. Twelve studies were included. Novel oral P2Y12 inhibitors significantly reduced the incidence of all-cause death (relative risk: 0.65, 95% confidence interval, 0.53–0.78), major adverse cardiac events [0.68 (0.56–0.83)], and stent thrombosis [0.56 (0.43–0.75)] without significant difference in bleeding (P = 0.11) compared with clopidogrel. Identical results were observed in the longer dual antiplatelet therapy (DAPT) and shorter-DAPT subgroups, albeit Chinese patients with ticagrelor treatment had a slight increase in bleeding (P = 0.08). Furthermore, the pooled relative risk ratio for each endpoint showed no significant difference between the longer-DAPT and shorter-DAPT subgroups. In conclusion, prasugrel and ticagrelor decreased the risk of all-cause death, major adverse cardiac events, and stent thrombosis without causing more bleeding events compared with clopidogrel in patients with STEMI undergoing PCI.