For patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI), antithrombotic therapy including oral anticoagulants and antiplatelets are indicated. The optimal combination is not known. We investigated the efficacy and safety of different antithrombotic strategies in patients with AF undergoing PCI. PUBMED and EMBASE were searched through September 2019 for randomized trials investigating the efficacy and safety of different antithrombotic strategies in patients with AF who underwent PCI and/or acute coronary syndrome. Nine antithrombotic strategies were compared including combinations of vitamin K antagonist (VKA) with dual antiplatelet therapy (DAPT) or P2Y₁₂ inhibitor, combinations of direct oral anticoagulants (DOAC) (apixaban, dabigatran, rivaroxaban, and edoxaban) with DAPT or P2Y₁₂ inhibitor (clopidogrel, prasugrel, and ticagrelor). The primary safety outcome was trial defined primary bleeding outcome. The primary efficacy outcome was trial defined major adverse cardiovascular events. Our search identified 5 eligible trials that enrolled a total of 11,532 patients and compared 9 treatment strategies. VKA + DAPT significantly increased bleeding when compared with most combinations (for example, vs VKA + P2Y₁₂ inhibitor: odds ratio 2.11; 95% confidence interval [1.76 to 2.52], p <0.001). Of all the combinations, apixaban + P₂Y₁₂ inhibitor showed the lowest bleeding risk (for example, vs VKA + P2Y₁₂ inhibitor: odds ratio 0.63; 95% confidence interval [0.51 to 0.78], p <0.001) and was ranked the best treatment. There were no significant differences in ischemic outcome of major adverse cardiovascular events between various antithrombotic regimens. In conclusion, in patients with AF undergoing PCI, apixaban + P2Y₁₂ inhibitors were associated with lowest bleeding compared with other regimens including other DOACs + P2Y₁₂ inhibitors with no increase in ischemic outcomes.