Background and objectives: Nasturtium officinale W.T.Aiton (Brassicaceae) is used as an edible vegetable in various parts of Iran. The aim of the present study was to investigate the protective activity of the methanolic extract of Nasturtium officinale against gamma-radiation-induced hepatotoxicity in terms of histopathological changes. Methods: Male C57 mice were divided into 10 groups. Groups 1 and 2 received saline solution intra-peritoneally (IP) for 15 days (subacute) and 2 h (acute) before whole body γ-irradiation (6 Gy). Groups 3 to 5 (subacute) and 6 to 8 (acute) received the extract at doses of 20 mg/kg, 50 mg/kg and 100 mg/kg body weight IP, respectively. Group 9 served as radiation group. Group 10 received nothing. Finally, sections of the liver tissue were evaluated for any histopathologic changes. Total phenolic and flavonoid contents were determined using Folin Ciocalteu andaluminium chloride methods. Results: Pre-treatment with 100 mg/kg body weight per day for 15 days and 2 h before γ-radiation significantly lowered incidence of inflammation (portal and periportal inflammation). Furthermore, liver cells necrosis, edema and congestion were slightly reduced. The total phenolic and total flavonoid contents of the extract were 11.3 ± 0.4 mg gallic acid equivalents and 9.4 ± 0.7 mg quercetin equivalents per gram of dried extract. Conclusion: This protection can be attributed to the presence of phenols and isothiocyanates in the extract of N. officinale which act as antioxidants and anti-inflammatory agents