THE CURRENT study was conducted to investigate the possible ameliorative effect of zinc oxide nanoparticles (ZnO-NPs) separately or in combination with Vitamin E on γ-radiation induced- oxidative stress in rats. Thirty-two Albino Rats were equally divided into four groups. Group (1) rats were injected with the saline (i.p). Group (2) rats were exposed to a single total body γ- radiation dose of (6Gy), Group (3) rats were daily i.p. injected with 10mg/kg b.w ZnO-NPs five days a week for two weeks after 24hrs of irradiation. Group (4) rats were treated as in group 3 in addition to oral administration of (100mg/kg b.w) of vitamin E for five days a week for two weeks. Data from the present study showed that γ- irradiation induced degenerative changes in the periportal hepatocytes, disruption of the renal vasculature and atrophy of the splenic lymphoid follicles. These histological changes were accompanied with significant elevation in liver, kidney and spleen tissue malondialdehyde (MDA) and a significant decline in glutathione (GSH) content. Data also demonstrated increased levels of plasma ALT, AST and ALP. There was a negative impact of exposure to γ- radiation on the renal function manifested by significant rise of plasma uric acid, urea and creatinine. Administration of ZnO-NPs prominently restructured the radiation-induced hepatic, renal and spleen damage. It also induced significant regularization of radiation-induced biochemical abnormalities. Co-administration of vitamin E with ZnO-NPs has potentiated its antioxidant effect.