BACKGROUND: In patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI), choosing the most appropriate antithrombotic treatment remains a dilemma. We aimed to compare the relative efficacy and safety outcomes of antithrombotic drugs in patients with AF after undergoing PCI or ACS. METHODS: Randomized controlled trials were systematically searched on PubMed, EMBASE, and the Cochrane Library. Five studies (11,532 patients) were included in the network meta-analysis. Trial sequential analysis (TSA) was performed to assess the reliability and conclusiveness of the meta-analysis comparing the dual antithrombotic therapy strategies with the triple antithrombotic therapy strategy. RESULTS: Compared with vitamin K antagonist + dual antiplatelet therapy, novel oral anticoagulant (NOAC) + P2Y12 inhibitor was associated with a significantly better trial-defined primary safety outcome (odds ratio: 0.53; 95% CI, 0.31-0.90) and the lowest probability of thrombolysis in myocardial infarction major bleeding and intracranial hemorrhage using the cumulative ranking technique. In patients omitting aspirin, TSA demonstrated conclusive evidence with significant decreases in all safety outcomes and inconclusive evidence with a nonsignificant increase in in-stent thrombosis (risk ratio: 1.32; TSA-adjusted 95% CI, 0.54-3.24) and myocardial infarction (risk ratio: 1.19; TSA-adjusted 95% CI, 0.84-1.68). CONCLUSIONS: In patients with AF receiving PCI or with ACS, NOAC + P2Y12 inhibitor was associated with the lowest bleeding risk but resulted in a statistically nonsignificant, numerically greater risk for stent thrombosis and myocardial infarction, suggesting that triple antithrombotic therapy should still be an option for certain patients at a high risk of stent thrombosis or myocardial infarction.