The exposure of ionizing radiation involve a highly orchestrated series of events that induced amplified by endogenous signaling and culminating in oxidative damage to deoxyribonucleic acid, lipids, proteins and many metabolites. Gallic acid ethyl ester is a major bioactive constituent of Hippophae rhamnoides L. leaves and extract prepared from it exhibited radio protective and pharmacological activity. Radio modifying properties of polyphenol compounds through free radical neutralizing have been reported earlier. The study aims to investigate the in silico and gamma-radio modifying action, oxidative stress estimation, histopathological and Immunohistopathological analysis of gallic acid ethyl ester at a radio protective dose and changes, if any, induced post irradiation. Male C 57 BL/6 mice (28 g-30 g) were administered Gallic acid ethyl ester (250 mg/kg b.w) orally 15 min prior to irradiation. Mice were sacrificed at different time points, plasma and tissues were studied for oxidative stress and pathological analysis. The gamma-radio modifying potential was assessed in terms of mitigating cyclooxygenase-2 expression and oxidative stress parameters levels in liver and kidney post irradiation. Our study suggested the potential use of gallic acid ethyl ester as gamma-radio modifying agent inhibits cyclooxygenase-2 expression and maintains the lipid peroxidation, superoxide, glutathione and alkaline phosphatase activity up to 8 h in comparison to irradiated mice. Moreover, in histopathological analysis, it showed that gallic acid ethyl ester protect and maintain the cellular architect in liver and kidney from the toxic effect of ionizing radiation. These in silico, pre-clinical biomolecules and histopathology result may be useful for study of the bioactive mechanism associated with radiation injury and to develop a potent formulation of gallic acid ethyl ester for clinical application against gamma-radiation.