A dual-pathway approach combining anticoagulation and antiplatelet (APT) therapy is challenging for the trade-off of benefits and bleeding risks. By selectively inhibiting the coagulation cascade-factor Xa or thrombin, novel oral anticoagulants (NOACs) combined with APT may be more conducive to achieve this balance. The study aimed to evaluate comprehensively the role of NOACs combined with APT in acute coronary syndrome (ACS) and AF undergoing PCI or complicating ACS. To identify relevant RCTs, a systematic literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. We summarized the results using the Mantel–Haenszel (M-H) random-effect models. The risk ratio (RR) value and 95% confidence intervals (CI) calculated were applied to dichotomous outcomes. Seventeen trials randomizing 49345 participants reported our predefined outcomes. For ACS patients, compared with control groups, NOACs combined with APT significantly reduced MACEs , ST, ischemic stroke and all-cause death , accompanied by increased TIMI major bleeding , trial-defined primary bleeding and ISTH major bleeding . For patients with AF undergoing PCI or complicating ACS, NOACs plus APT markedly decrease the risk of bleeding compared with the control groups, including TIMI major bleeding , trial-defined primary bleeding , ISTH major bleeding and ISTH CRNM bleeding. However, there were no obvious differences in all efficacy outcomes. These findings support the application of NOACs combined with APT in patients with ACS and AF undergoing PCI or complicating ACS; however, appropriate regimens should be designed to obtain the maximal benefit and balance the bleeding risk in clinical practice.