Background: New randomized, controlled trials have become available on oral P2Y ₁₂ inhibitors in acute coronary syndrome. We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor, and clopidogrel in acute coronary syndrome by a meta-analysis of randomized controlled trials. Methods: We performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from 12 randomized controlled trials including a total of 52 816 patients with acute coronary syndrome. Results: In comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72–0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75–0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80–1.01] and HR, 0.92 [95% CI, 0.84–1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94–1.29] and 1.12 [95% CI, 0.98–1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67–0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78–1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel (28%–50% range of reduction). In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01–1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04–1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored. Conclusions: Prasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison with clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42019155648.