T HE PRESENT study was designed to evaluate the radio-protective effects of Saccharomyces cerevisiae-fermented garlic extract (FGE) on γ-irradiation-induced acute toxicity in rats' brain and liver. The rats were divided into four groups, Group I (C; control group), Group II (FGE), III (R: irradiated rats), Group IV (FGE+R). In C, and R groups rats were administered orally with 1 ml of water, and in FGE, and FGE+R groups, rats administered orally with 1 ml of FGE. At day 21, R and FGE+R groups were exposed to a single shot of whole-body gamma irradiation (6 Gy). The results showed that γ-irradiation significantly increased the activity of the hepatic enzymes; ALT, AST, ALP, GGT, and the levels of total-cholesterol (TC), and triglycerides (TG) in the serum. In addition, the activity of SOD, and GSH-Px were significantly decreased, with alteration in the trace elements levels were observed in the brain and liver cytosolic fractions. Moreover, the levels of MDA, and the pro-inflammatory markers; TNF-α, IL-1β, IL-6 and caspase-3 activity were significantly elevated, GSH content was significantly decreased (P<0.001), the gene expression ratios of NF-κB and STAT3 showed significant up-regulation (P<0.001), as well as, DNA fragmentations were observed in brain and liver tissues. FGE pre-treatment has significantly ameliorated the changes in all these studied parameters. The histopathological investigations confirmed these biochemical changes in the brain and liver tissues. These findings could suggest that the bioactivities of FGE showed neuro-hepato-protective effects on acute toxicity of gamma irradiation, by improving the antioxidant, anti-inflammatory and anti-apoptotic activities associated with regulation of the NF-κB and STAT3 signaling pathway in rats' brain and liver.