A review.In conclusion, the vulnerability of the brain to oxidative stress (OS) holds a pivotal significance in acute neurol. injuries as well as in the initiation and progression of epilepsy conditions.Seizures can induce OS, while chronic OS can contribute to neuronal excitability, inflammation, and neuronal cell loss, all of which contribute to epilepsy.However, the current evidence on the use of antioxidants for epilepsy treatment is limited and has produced mixed results.Clin. trials of vitamin E, N-acetylcysteine, ebselen, and tirilazad have primarily focused on symptomatic treatment of epilepsy rather than investigating their potential for modifying the disease.To achieve significant clin. benefits in chronic and progressive neurol. conditions, such as epilepsy, it is necessary to administer antioxidant therapy at an early stage for a prolonged duration.Nonetheless, another significant challenge in utilizing antioxidants efficiently is their short life and limited BBB permeability.Our previous report suggested that the antioxidant defense system is not homogeneously activated throughout the brain but possibly has a region-specific antioxidant defense, suggesting that most antioxidant-based therapies failed to exhibit prolonged effects in preclin. and clin. investigations.Thus, targeting the Keap1-Nrf2 pathway, a master regulator of antioxidant and anti-inflammatory responses, is a promising therapeutic approach, as revealed in various preclin. investigations.The activation of Nrf2 enhances antioxidant and anti-inflammatory responses and provides neuroprotection.Collectively, these therapeutic strategies for targeting OS via activation of Nrf2 to orchestrate antioxidant and anti-inflammatory responses in epilepsy show exciting avenues, however, further research and strategic clin. trials are required to fully comprehend the relationship between OS and epilepsy to understand and mitigate disease development and progression by validating efficacy and safety to achieve maximum clin. benefits.