Background: Extensive research has been focused on radiation induced brain injury. Animal and human studies have shown that flavonoids have remarkable toxicological profiles. This study aims to investigate the neuroprotective effects of hesperidin in an experimental radiation induced brain injury. Materials and Methods: 32 adult male Wistar-Albino rats were randomly divided into 4 groups (control, hesperidin, radiation, and radiation+hesperidin groups; 8 rats in each group). 200 mg/kg  doses of hesperidin were administered to the animals in the hesperidin and radiation+ hesperidin groups, radiation and radiation+ hesperidin groups were exposed to a dose of 20 Gy cranium region. Tissue samples, and biochemical levels of tissue injury markers in four groups were compared. Results: In all measured parameters of oxidative stress, administration of hesperidin significantly demonstrated favorable effects. Both plasma and tissue levels of malondialdehyde and total antioxidant status significantly changed in favor of antioxidant activity. Histopathological evaluation of the tissues also demonstrated significant decrease in cellular degeneration and infiltration parameters after hesperidin administration. Conclusion: This Hesperidin demonstrated significant neuroprotection after radiation induced brain injury. Further studies with different experimental settings including neurological outcome are required to achieve conclusive results.