The present study aimed to assess the radioprotective effects of curcumin in combination with quercetin against radiation-induced changes in some histopathological, immunohistochemical, and biophysical parameters. The current study rats had been grouped into control, curcumin, quercetin, gamma irradiated (8 Gy fractionated dose), curcumin pretreated irradiated, quercetin pretreated irradiated, and both curcumin and quercetin pretreated irradiated groups. Gamma radiation exposure resulted in hepatic and renal damage. Administration of curcumin along with quercetin before gamma radiation exposure reduced the liver and kidney damage caused by radiation, demonstrating the radioprotective effects of both curcumin and quercetin antioxidants through free radicals scavenging effects, P53, and TNF-α inhibition, and structural changes measured by Fourier Transform Infrared (FTIR). The cellular damage by gamma radiation is greatly mitigated by administration of curcumin and quercetin before radiation exposure.