β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study is carried out to evaluate the effect of gamma irradiated β-glucan (Iβ-glucan) extracted from mushroom in modulating diethylnitrosamine (DEN)-induced immune response and mitochondrial dysfunction in renal toxicity. Rats were divided into 4 groups. Group I: control group, group II: animals received the DEN (20mg/kg) for 6 weeks, group III: was gavaged Iβ-glucan (65mg/kg b. wt.) for 6 weeks, group IV: received as group II and then treated as group III. Exposure to DEN induced a change in the levels of cytokines (IFN-γ, TNF-α, IL-6) and nephrotoxicity, which was proved by significant elevated levels of creatinine and urea along with upregulation of mRNA cytochrome P450 (2E1) and downregulation in mitochondrial enzymes complex I and II. Treatment with Iβ-glucans post DEN-exposure significantly improved the disturbances in all the ++ tested parameters. It could be concluded that Iβ-glucan treatment exerts a potential biological effect on both mitochondrial and immune system dysfunction caused by the DEN- induced renal toxicity in rats. It is considered for further trials.