The efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) combined with antiplatelet drugs in patients with peripheral artery disease remain largely unknown. The aim of this meta-analysis was to explore the effects of NOACs combined with antiplatelet drugs versus antiplatelet drugs alone in this population. A comprehensive search of randomized controlled trials published in PubMed, EMBASE, Web of Science, and the Cochrane Library in 30 September 2020 and before. According to the I2 statistic, a random or fixed-effect model was used to analyze the safety and effectiveness of NOACs combined with antiplatelet drugs in peripheral artery disease patients. Three RCTs met the inclusion criteria, with a total sample size of 11,761 participants. Compared with antiplatelet drugs alone, NOACs combined with antiplatelet drugs resulted in lower risk of ischemic stroke events (OR = 0.75, 95%CI 0.57-0.98, p = 0.03), while other treatment effects were not worse than those of single antiplatelet drugs (p ≥ 0.05). In addition, although compared with single antiplatelet drugs alone, NOACs combined with antiplatelet drugs had a higher risk of major bleeding and clinically related nonmajor bleeding, their risk was not higher for intracranial hemorrhage, which may endanger the life of patients, or for fatal bleeding. In summary, for peripheral artery disease patients, a combination of NOACs plus antiplatelet drugs may offer additional benefit in reducing ischemic stroke outcome, yet it may increase the risk of bleeding.