Background: Gender is a well-recognized risk factor in atrial fibrillation (AF)-related ischemic stroke. The association of gender with the use of oral anticoagulants (OACs) and prognosis remains unknown. Methods: The National Health Insurance Research Database in Taiwan identified 203,775 patients with AF aged \ge20 years from 2012 to 2018, with 55.4% of males. Our main study cohort included 67,426 patients using OACs. The study endpoints include death, ischemic stroke, intracranial hemorrhage, major bleeding, and composite adverse events. Results: Significant differences were found in baseline characteristics between sexes. Female patients with AF were older and had higher CHA{}_2DS{}_2-VASc and HAS-BLED scores. Non-vitamin K antagonist oral anticoagulant (NOAC) use was more prominent in females while the use of warfarin was similar in both sexes. The distribution of baseline characteristics between the warfarin and NOAC groups in both sexes was much alike. Among the whole study cohort, NOAC was associated with a decreased risk of clinical endpoints compared to warfarin, which remained the same in subgroup analyses of both sexes. Additionally, a greater risk reduction of ischemic stroke with NOAC was observed in female patients compared to male patients (adjusted hazard ratio: 0.517 in males, 0.425 in females, interaction p = 0.040). Conclusions: This nationwide cohort demonstrated the differences between male and female patients with AF, including baseline characteristics, risk profiles, and medication use. Despite great differences in baseline demographic data, NOAC was associated with better clinical outcomes compared to warfarin in both sexes, and females benefited more than males in preventing ischemic stroke using NOACs.