The 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) and III (R: irradiated rats) rats administered orally with 1 ml of water. Group II (FGE) and IV (FGE+R): rats administered orally with 1 ml of fermented garlic extract (FGE).  Then after 21 days of treatment, rats of groups III, and IV 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 and Triglycerides 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 fragmentation were also observed in brain and liver tissues.  FGE pre-treatment has significantly ameliorated the changes in all these studied parameters.  These findings could suggest that the bioactivities of FGE showed neuro-hepato-protective effects on acute toxicity of gamma irradiation by improving the antioxidant system, anti-inflammatory and anti-apoptotic activities associated with regulation of the NF-κB and STAT3 signaling pathway in rats' brain and liver.