Background: Peripheral arterial disease (PAD) increases cardiovascular (CV) morbidity and mortality, but remains underdiagnosed and undertreated. Several trials support low-dose direct oral anticoagulant (DOAC) use in PAD treatment, although this has yet to be widely adopted in clinical practice. Patients and methods: We conducted a retrospective study of patients who underwent ankle-brachial index testing (ABI) from 1996 - 2020 at Mayo Clinic. We included patients with PAD defined by abnormal ABI (<1.0 or >/=1.4). Primary outcomes evaluated were myocardial infarcts (MI), ischemic strokes (IS), critical limb ischemia (CLI)/amputation, bleeding events and all-cause mortality. DOAC and warfarin use were each compared to no anticoagulant use for the outcomes using univariate analysis and multivariate analysis. Results: 22,162 patients had abnormal ABI readings; 1,266 were on warfarin and 269 were on DOAC for any indication. Both the DOAC and warfarin groups showed significant a decrease in all-cause mortality. The DOAC group showed superior mortality outcomes with HR 0.50 [95% CI 0.40-0.63], p-value <0.001 compared to warfarin with HR 0.88 [95% CI 0.81-0.96], p-value <0.004. There appeared to be a similar trend for MI and CLI/amputation however this was not statistically significant. IS was similar with only warfarin being statistically significant. The DOAC group had improved bleeding outcomes compared to the warfarin group, HR 0.53 (95% CI 0.24-0.85), p-value 0.007. Notably, the addition of ASA for both AC groups resulted in significant HR >1. Conclusions: Our study shows that anticoagulation use, particularly DOACs, is associated with decreased all-cause mortality in patients with PAD. There appears to be a favorable trend for DOACs in MI, IS and CLI/amputation. Lastly, DOACs were found to have superior outcomes with bleeding events.