Abstract Aims This study compared the risk of major bleeding between atrial fibrillation (AF) patients who took non-vitamin K antagonist oral anticoagulants (NOACs) and antiepileptic drugs (AEDs) concurrently and those who took only NOACs. Methods and results We performed a retrospective cohort study using Taiwan National Health Insurance database and included AF patients who received NOAC prescriptions from 1 June 2012 to 31 December 2017. The major bleeding risks of person-quarters exposed to NOAC and 11 concurrent AEDs (carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, valproic acid, and zonisamide) were compared with person-quarters exposed to NOAC alone. Adjusted incidence rate differences between NOAC with or without concurrent AEDs were estimated using Poisson regression models weighted by the inverse probability of treatment. Among 104 319 patients (age 75.0 ± 10.3 years; men, 56.2%), 8546 major bleeding events occurred during 731 723 person-quarters with NOAC prescriptions. Concurrent AED use was found in 15.3% of NOAC-treated patients. Concurrent use of NOAC with valproic acid, phenytoin, or levetiracetam increased adjusted incidence rates per 1000 person-years of major bleeding more significantly than NOAC alone: 153.49 for NOAC plus valproic acid vs. 55.06 for NOAC alone [difference 98.43, 95% confidence interval (CI) 82.37–114.49]; 135.83 for NOAC plus phenytoin vs. 54.43 for NOAC alone (difference 81.4, 95% CI 60.14–102.66); and 132.96 for NOAC plus levetiracetam vs. 53.08 for NOAC alone (difference 79.88, 95% CI 64.47–95.30). Conclusion For AF patients, the concurrent use of NOACs and valproic acid, phenytoin, or levetiracetam was associated with a higher risk of major bleeding.