Mechanical thrombectomy (MT) is one of the main treatments for acute ischemic stroke (AIS) in patients on effective anticoagulation. The use of direct oral anticoagulants (DOA) has increased, given their efficacy and safety profile compared to vitamin K antagonists (VKA). We compared procedural and clinical outcomes of MT in patients on DOA and VKA treatment before stroke onset. We analyzed 2 groups from the Endovascular Treatment in Ischemic Stroke prospective registry: patients on DOA and patients on VKA treated by MT without thrombolysis. Generalized linear mixed models including center as random effect were used to compare angiographic (rates of reperfusion at end of procedure, number of passes >2, procedural complications) and clinical (favorable and excellent outcome, 90-day all-cause mortality, and hemorrhagic complications) outcomes according to anticoagulation subgroups. Comparisons were adjusted for prespecified confounders (age, admission NIH Stroke Scale score) as well as for meaningful baseline between-group differences. Among 221 patients included, more DOA-treated patients (n = 115, 52%) achieved successful (modified Thrombolysis in Cerebral Infarction score [mTICI] 2b/3) or near complete (mTICI 2c/3) reperfusion at the procedure end than did VKA-treated patients, with an adjusted odds ratio (OR) for DOA vs VKA of 3.27 (95% confidence interval [CI], 1.40–7.65) and 2.00 (95% CI, 1.08–3.73), respectively. DOA-treated patients had a lower 90-day mortality risk with an adjusted OR of 0.47 (95% CI, 0.24–0.89) and a better excellent outcome OR of 2.40 (1.10–5.27). There was no significant between-group difference in hemorrhagic or procedural complications. The study highlights the benefits of DOA compared to VKA. Regarding mortality, excellent outcomes, and recanalization rate, DOA appears to provide a favorable setting for MT treatment in AIS.