Protection against whole-body γ-irradiation (WBI) of Swiss albino mice intraperitonally injected with umbelliferone (UMB), in terms of mortality of irradiated animals, DNA damage and antioxidant status in liver and intestine (jejunum) has been investigated. Swiss albino mice were administered UMB (30mg/kg b.wt.), once daily for 5 consecutive days and 1 hour after the last administration of UMB on the sixth day, animals were exposed to whole-body irradiation (10Gy). Radiation-induced augmentation of lipid peroxidation (TBARS) was significantly ameliorated by UMB pretreatment. The present findings showed that radiation-induced depletion of reduced glutathione (GSH) level as well as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities were significantly prevented by UMB administration. Further, it has been found that DNA damage was increased in the blood lymphocytes of WBI mice. UMB (30mg/kg b.wt.) pretreatment significantly prevented radiation-induced DNA damage in irradiated mice lymphocytes. Moreover, UMB pretreatment elevated the radiation LD₅₀ from 8.4 to 9.5 having dose-modifying factor of 1.03. Irradiated mice showed distortion of villus anatomy with evidence of cryptitis in jejunum sections and hepatocyte degeneration in liver sections. Administration of UMB before radiation exposure prevented crypt cells damage and hepatocyte degeneration. Thus, UMB pretreatment prevented radiation-induced lipid peroxidation, DNA damage, restored tissue antioxidant status and histopathological changes in Swiss albino mice.