Abstract Background: Topiramate is a drug used to treat seizures in patients with epilepsy, however, kidney damage may result after its long-term use. The mechanisms of damage are variable and can affects all renal cellular components. Aim of Study: Treatment with an antioxidant, such as vitamin C, may help prevent this renal damage. In this study, we used histological, ultrastructural, and biochemical ap-proaches to detect the renal affection caused by topiramate treatment and to evaluate the role of vitamin C in protection against topiramate-induced nephrotoxicity. Material and Methods: Forty adult male albino rats treated daily for six weeks and divided equally to four groups: Group I (control group), group II supplemented orally with vitamin C (10mg/kg/day), group III treated orally with topiramate (100mg/kg/day), and group IV received vitamin C (10mg/ kg/day) 2 hours prior to topiramate (100mg/kg/day) treatment. Results: Examination of the kidney tissue of group III showed distortion of the renal glomeruli and tubules. In addition, topiramate significantly elevated the levels of serum urea, creatinine, lipocalin, indoxyl sulphate, and tissue malond-ialdehyde (MDA), and caused significant reduction in tissue superoxide dismutase (SOD) and catalase (CAT). However, group IV showed improvement in the renal glomeruli and tubules with significant improvement in serum urea, creatinine, lipocalin, indoxyl sulphate and tissue oxidative stress markers. Conclusion: The data presented in this work shows that topiramate may be a toxic therapeutic agent however, vitamin C supplementation may aid in protection against topiramate-induced nephrotoxicity.