HESPERETIN (HPT) is a natural flavonoid utilizing pharmacological activities such as anti-oxidation, anti-inflammation. Its effect on nephrotoxicity and its precise mechanism remains unclear. The objective of this study is to explore the potential reno protective efficacy of HPT on nephrotoxicity triggered by γ-rays-exposure in mice. Thirty-two male mice were randomly divided into four groups. The control group (vehicle), HPT group (60 mg/ kg daily over 14 days), irradiated (IRR) group received vehicle+ γ-rays (6Gy), and HPT+ γ-rays group (mice treated with HPT before exposure to γ-rays). Serum urea and creatinine, renal malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) levels were determined. Damage to the proximal and distal tubules were observed using histopathological examination. The results showed that HPT significantly elevated renal GSH, SOD, CAT and GPx and decreased the MDA, urea, creatinine levels, and the inflammatory markers. Histopathological findings showed glomerulus atrophy and dilated renal tubules include enlarged capsular space, degenerating variations and hyaloid casts. Aggregation of leukocytes in renal tubules may be shown in some cases. Exposing mice to γ-rays exacerbated oxidative stress, malondialdehyde, and kidney injury. Mice can be protected by giving HPT, which protects against gamma hazardous and this is an important feature in protecting or treating acute kidney illnesses.