Studies have linked on-treatment platelet reactivity (PR) to adverse clinical outcomes. Because new P2Y₁₂ inhibitors (prasugrel and ticagrelor) have been predominantly tested against clopidogrel, data on pharmacodynamic comparisons between these 2 drugs are scarce. We compared ticagrelor with prasugrel in a network meta-analysis. PubMed, Cochrane, and EMBASE were searched for studies assessing PR in patients with coronary artery disease treated with ticagrelor or prasugrel. All studies using prasugrel and/or ticagrelor providing platelet function measurement data using VerifyNow P2Y12 reaction units (PRUs), platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein phosphorylation, or maximal platelet aggregation (MPA) by light transmission aggregometry were considered eligible. Mixed treatment comparison models directly compared ticagrelor and prasugrel and indirectly compared them using clopidogrel as a comparator with data presented as mean difference (95% confidence interval). Data were extracted from 29 studies, including 5,395 patients. Compared with clopidogrel 75 mg, both prasugrel 10 mg and ticagrelor 90 mg twice daily were associated with lower PRU (mean difference −117 [−134.1, −100.5] and −159.7 [−182.6, −136.6], respectively), a lower PRI (−24.2 [−28.2, −20.3] and −33.6 [−39.9, −27.6], respectively), and lower MPA (−11.8 [−17, −6.3] and −20.7 [−28.5, −12.8], respectively). Similar results were obtained with clopidogrel 150 mg. Ticagrelor 90 mg twice daily was associated with lower PRU (−42.5 [−62.9, −21.9]), lower PRI (−9.3 [−15.6, −3.5]), and lower MPA (−8.9 [−16.4, −1.2]) compared with prasugrel 10 mg. In conclusion, our meta-analysis suggests that ticagrelor achieved significantly lower on-treatment PR compared with prasugrel, with both being superior to clopidogrel standard or high dose.