A Phase II clinical trial sought to determine whether there is an ideal delay time to start treatment with a direct oral anticoagulant (DOAC) after an atrial fibrillation–associated acute ischemic stroke. The study, which was conducted at acute care hospitals in Texas, included patients who had a mild to moderate ischemic stroke with atrial fibrillation and were prescribed a DOAC within 14 days of stroke onset. Participants were randomized to one of four groups for a treatment start date, starting at 3-4 days after stroke onset (group 1), day 6 (group 2), day 10 (group 3), and day 14 (group 4). Among the 200 patients enrolled in the study, group 1 had no ischemic events, while there were three events in group 2 and two each in groups 3 and 4. Groups 1, 2, and 3 each had one hemorrhagic event, while group 4 had none. The posterior probability for being the optimal day for treatment initiation ranged from 0.41 in the group 1 to 0.15 in group 4. Although the study did not identify a clearly superior day on which to start DOAC treatment for secondary stroke prevention in this patient population, the findings point to the benefits of starting treatment earlier rather than later in the 14 days following a stroke.