The purpose of this study was to evaluate the efficacy and safety of direct oral anticoagulants vs. warfarin for portal vein thrombosis treatment. This was a single-center, retrospective study. Adult patients initiated on a direct oral anticoagulant or warfarin for treatment of a new portal vein thrombosis were included. The primary failure outcome was the absolute difference in recurrent thromboembolic events 90 days following initiation of a direct oral anticoagulant vs. warfarin. The primary safety outcome was the absolute difference in bleeding events 90 days following initiation of a direct oral anticoagulant vs. warfarin. Descriptive statistics, Fisher's exact, and Student's t-tests were utilized as appropriate. Thirty-three patients were included. Thirteen (39.4%) patients received direct oral anticoagulants, and 20 (60.6%) received warfarin. None of the patients receiving direct oral anticoagulants experienced a primary failure event compared to four receiving warfarin (P < 0.001). None of the patients receiving direct oral anticoagulants experienced a primary safety event vs. one receiving warfarin (P < 0.001). Direct oral anticoagulants appear to be effective and safe in the treatment of portal vein thrombosis and in preventing recurrent thromboembolic events. Future studies with larger sample sizes are warranted to confirm direct oral anticoagulants' efficacy in portal vein thrombosis.