ABSTRACT Background: Epilepsy is one of the most common diseases of the central nervous system that leads to seizures and neurobiological, cognitive, and social consequences. Studies have shown that vitamin D has a critical role in brain development and neuroprotection. According to another study, exercise effectively improves a variety of brain functions. Objective: The current work is designed for the assessment of the beneficial effects of vitamin D and exercise in a rat model of epilepsy disease. Materials and Methods: 30 healthy adult male albino rats were divided equally into five groups: the control group, the epilepsy-induced group by pentylentetrazole, the epileptic group with vitamin D, the epileptic group with exercise, and the epileptic group with both vitamin D and exercise. The following parameters were assessed in rat brain tissues: BDNF and GABA. Serum levels of IL-1β, MDA, TNF-α, GSH, and GABA were also estimated in addition to cognitive function tests and histopathological examination of rat brain tissues. Results: In the epileptic group, there was a significant increase in IL-1β, TNF-α, and MDA levels. In addition to a significant decrease in GSH, GABA, and BDNF levels. Treatment with either vitamin D or exercise significantly improved biochemical abnormalities, cognitive dysfunction, and the histopathological picture of the brains of epileptic rats, with the best results in the combined vitamin D and exercise-treated group. Conclusions: These data suggest that combined vitamin D and exercise could be considered as a potential and effective line for treating epilepsy disease. Keywords: Vitamin D, Exercise, epilepsy disease, pentylentetrazole.