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Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is standard for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), yet real-world comparisons of ticagrelor and prasugrel remain limited. We evaluated their relative effectiveness and safety using the TriNetX Global Collaborative Network (2010-2024). Adult ACS patients receiving prasugrel or ticagrelor within 24 h post-PCI were included. The primary endpoint was a 1-year composite of all-cause mortality, myocardial infarction (MI), and cerebral infarction; secondary endpoints included individual components, major bleeding, and repeat revascularization. Propensity score matching balanced baseline characteristics, with subgroup and sensitivity analyses assessing robustness. Among 14,895 matched pairs (n = 29,790) from 126,273 patients, prasugrel was associated with lower risk of the composite endpoint (HR 0.641; 95% CI 0.613-0.671), all-cause mortality (HR 0.557; 95% CI 0.487-0.637), and MI (HR 0.648; 95% CI 0.616-0.680), without increased bleeding (HR 0.945; 95% CI 0.824-1.084). Repeat revascularization was higher with prasugrel (HR 1.791; 95% CI 1.639-1.957). Effects were consistent across subgroups. In this real-world setting, prasugrel demonstrated superior effectiveness over ticagrelor in reducing mortality and ischemic events without increasing the risk of bleeding, although higher rates of repeat revascularization warrant further study. These findings support prasugrel as a potentially preferred P2Y12 inhibitor in selected ACS patients undergoing PCI.