Background An increased risk of recurrent stroke is noted in patients with atrial fibrillation despite direct oral anticoagulant (DOAC) use. We investigated the efficacy and safety of treatment with each of 4 different DOACs or warfarin after DOAC failure. Methods and Results We retrospectively analyzed patients with atrial fibrillation with ischemic stroke despite DOAC treatment between January 2002 and December 2016. The different outcomes of patients with DOAC failure were compared, including recurrent ischemic stroke, major cardiovascular events, intracranial hemorrhage and subarachnoid hemorrhage, mortality, and net composite outcomes according to switching to different DOACs or vitamin K antagonist after index ischemic stroke. We identified 3759 patients with DOAC failure. A total of 84 patients experienced recurrent ischemic stroke after switching to different oral anticoagulants, with a total follow‐up time of 14 years. Using the vitamin K antagonist group as a reference, switching to any of the 4 DOACs was associated with a 69% to 77% reduced risk of major cardiovascular events (adjusted hazard ratio [aHR], 0.25 [95% CI, 0.16–0.39] for apixaban, 0.23 [95% CI, 0.14–0.37] for dabigatran, 0.23 [95% CI, 0.09–0.60] for edoxaban, and 0.31 [95% CI, 0.21–0.45] for rivaroxaban), and a 69% to 83% reduced risk of net composite outcomes (aHR, 0.25 [95% CI, 0.18–0.35] for apixaban, 0.17 [95% CI, 0.11–0.25] for dabigatran, 0.31 [95% CI, 0.17–0.56] for edoxaban, and 0.31 [95% CI, 0.23–0.41] for rivaroxaban). Conclusions In Asian patients with DOAC failure, continuing DOACs after index stroke was associated with fewer undesirable outcomes than switching to a vitamin K antagonist. Alternative pharmacologic and nonpharmacologic strategies warrant investigation.