Background-—There is insufficient evidence on the effect of statins, particularly high-intensity statins, in patients with acute ischemic stroke and atrial fibrillation. We investigated the impact of statins on the outcomes in these patients, including those who might be vulnerable to statin therapy and those without clinical atherosclerotic cardiovascular diseases. Methods and Results-—A total of 2153 patients with acute ischemic stroke and atrial fibrillation were enrolled in the present nationwide, multicenter, cohort study. The primary composite end point was the occurrence of net adverse clinical and cerebral events (NACCE; death from any cause, stroke, acute coronary syndrome, or major bleeding) over a 3-year period based on statin intensity. NACCE rates were lower in patients receiving low-to moderate-intensity (adjusted hazard ratio 0.64; 95% CI: 0.52-0.78) and high-intensity statins (hazard ratio 0.51; 95% CI 0.40-0.66) than in those not receiving statin therapy. High-intensity statins were associated with a lower risk for NACCE than low-to moderate-intensity statins (hazard ratio 0.76; 95% CI 0.59-0.96). Subgroup analyses showed that the differences in hazard ratio for 3-year NACCE favored statin use across all subgroups, including older patients, those with low cholesterol levels, patients receiving anticoagulants, and patients without clinical atherosclerotic cardiovascular diseases. Magnified benefits of high-intensity statins compared with low-to moderate-intensity statins were observed in patients who underwent revascularization therapy and those under 75 years of age. Conclusions-—Statins, particularly high-intensity statins, could reduce the risk for NACCE in patients with acute ischemic stroke and atrial fibrillation; this needs to be further explored in randomized controlled trials.