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The best method of anticoagulation for patients with peripheral artery disease (PAD) is still a topic of interest for physicians. We conducted a meta-analysis to compare the effects of direct oral anticoagulants (DOACs) with those of vitamin-K-antagonist (VKA) anticoagulants in patients with peripheral artery disease. Five databases (Medline (via PubMed), EMBASE, Scopus, Web of Science, and CENTRAL) were searched systematically for studies comparing the effects of the two types of anticoagulants in patients with PAD, with an emphasis on lower-limb outcomes, cardiovascular events, and mortality. In PAD patients with concomitant non-valvular atrial fibrillation (NVAF), the use of DOACs significantly reduced the risk of major adverse limb events (HR = 0.58, 95% CI, 0.39–0.86, <i>p</i> < 0.01), stroke/systemic embolism (HR 0.76; 95% CI 0.61–0.95; <i>p</i> < 0.01), and all-cause mortality (HR 0.78; 95% CI 0.66–0.92; <i>p</i> < 0.01) compared with warfarin, but showed similar risks of MI (HR = 0.81, 95% CI, 0.59–1.11, <i>p</i> = 0.2) and cardiovascular mortality (HR = 0.77, 95% CI, 0.58–1.02, <i>p</i> = 0.07). Rivaroxaban at higher doses significantly increased the risk of major bleeding (HR = 1.16, 95% CI, 1.07–1.25, <i>p</i> < 0.01). We found no significant difference in terms of revascularization (OR = 1.49, 95% CI, 0.79–2.79, <i>p</i> = 0.14) in PAD patients in whom a poor distal runoff was the reason for the anticoagulation. DOACs have lower rates of major limb events, stroke, and mortality than VKAs in PAD patients with atrial fibrillation. Rivaroxaban at higher doses increased the risk of major bleeding compared with other DOAC drugs. More high-quality studies are needed to determine the most appropriate anticoagulation regimen for patients with lower-limb atherosclerosis.