Background: Ionizing radiation is known to generate reactive oxygen species. This study was carried out to investigate the efficacy of mulberry fruit against γ-irradiation induced oxidative stress in rats. Materials and methods: Male albino rats were divided into four groups, Group (I): (control group) rats fed on balanced diet for 4 weeks, Group (II): rats fed on balanced diet contained 5% mulberry fruits powder (MFP), Group (III): rats were exposed at the 1st week of the experiment to fractionated γ-irradiation dose of 8 Gy administered as 2 Gy, every other day and fed on balanced diet for 4 weeks, and Group (IV): irradiated rats fed on balanced diet contained 5% mulberry fruits powder, at the end of the experiment, animals from each group were sacrificed, 24 hrs post the last dose of treatment, six rats from each group were sacrificed. Blood samples were taken and analyzed for Lipid peroxides as malondialdehyde (MDA) level, Xanthine Oxidoreductase system (XO and XDH), Glutathione (GSH) content,  Superoxide dismutase (SOD), catalase (CAT), Aspartate Transaminase (AST), Alanine Transaminase (ALT), Gamma Glutamyl Transferase (GGT), Alkaline Phosphatase (ALP) activities and total bilirubin in rats. Results: The results showed that, irradiation induced high significant decrease in hepatic Glutathione contents (GSH), Xanthine Dehydrogenase (XDH), Superoxides Dismutase (SOD) and Catalase (CAT) activity. Moreover, a remarkable increase in the Malondialdehyde (MDA) concentration, xanthine oxidase activity (XO), the activity of some liver enzymes was observed in γ-irradiated rats. In contrast, administration of Mulberry Fruit Powder (MFP) to γ-irradiated rats was found to offer protection against γ-irradiation induced oxidative stress, by elevating the activity of antioxidant enzymes, enhancing liver function. All results in this study suggested that mulberry fruit had high potential to be developed as radio protective agent. Conclusion: Therefore, MFP could have a beneficial role in modulating oxidative stress by improving the natural antioxidant mechanism.