BACKGROUND: Epilepsy, a neurological disorder characterized by recurrent seizures, presents considerable difficulties in treatment, particularly when dealing with drug-resistant cases. Dapsone, recognized for its anti-inflammatory properties, holds promise as a potential therapeutic option. However, its effectiveness in epilepsy requires further investigation. The aim of this study is to explore the effects of dapsone on seizure activity and neuroinflammation, particularly through the nuclear factor erythroid-2-related factor (Nrf2)/ Heme Oxygenase 1 (HO-1) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) pathways, to better understand its therapeutic potential. METHODS: To evaluate the effects of dapsone, two seizure models were utilized in mice: pentylenetetrazole (PTZ)-induced clonic seizures and maximal electroshock (MES)-induced generalized tonic-clonic seizures (GTCS) in mice. The impact of dapsone on neuroinflammatory markers and oxidative stress pathways, specifically Nrf2/HO-1 and NLRP3, as well as interleukin-1β (IL-1β), IL-8, and IL-18, was assessed using Western blotting and ELISA techniques. RESULTS: In this study, dapsone (2, 5, 10, and 20 mg/kg, ip) showcased a significant increase in clonic seizure threshold following intravenous infusion of PTZ. Notably, doses of 5, 10, and 20 mg/kg exhibited increased latency and decreased the number of seizures. Additionally, dapsone at 10 and 20 mg/kg prevented the incidence of GTCS and subsequent mortality in the MES model. Furthermore, Dapsone demonstrated modulation of Nrf2/ HO-1 and NLRP3 IL-1 β/IL-18 pathways. CONCLUSION: This study highlights the therapeutic potential of dapsone in epilepsy, emphasizing the involvement of Nrf2/HO-1 and NLRP3 pathways. These findings provide a foundation for future clinical research aimed at developing dapsone-based therapies for drug-resistant epilepsy.