Post-stroke epilepsy (PSE) poses a significant challenge despite advances in stroke treatment. This study compares the efficacy of the novel anti-seizure medication (ASM) Perampanel with the classical ASM Oxcarbazepine in treating PSE.This prospective randomized controlled trial recruited PSE patients from September 2022 to January 2024 across multiple hospitals. Patients were randomly assigned to receive either Perampanel or Oxcarbazepine monotherapy. Baseline seizure frequency was measured over three months prior to treatment. Efficacy was assessed at six months, with a ≥ 50 % reduction in seizure frequency deemed effective. Perampanel was considered non-inferior to Oxcarbazepine if its lower 95 % confidence limit for efficacy was above 80 % of Oxcarbazepine's six-month seizure freedom rate. Intention-to-treat analysis and Kaplan-Meier methods evaluated retention rates and side effects.A total of 67 patients were included in this study: 33 patients in the Perampanel group (26 males, 78.8 %; 7 females, 21.2 %) and 34 patients in the Oxcarbazepine group (26 males, 76.5 %; 8 females, 23.5 %). There were no statistically significant differences in the baseline data between the two groups. This indicates that the groups are comparable. Treatment efficacy was 75.0 % and 78.8 % in the Perampanel and Oxcarbazepine groups at three months, and 80.6 % and 75.0 % at six months, respectively. At six months, the lower limit of the 95 % confidence interval for efficacy in the Perampanel group was higher than the prespecified non-inferiority threshold, indicating that Perampanel was noninferior than Oxcarbazepine. The rates of drug retention and adverse effects were similar in the two groups, with no statistically significant difference (P > 0.05).Perampanel is noninferior to Oxcarbazepine and is considered a good option for the management of post-stroke epilepsy.Copyright © 2025. Published by Elsevier Ltd.