The present study evaluated the possible ameliorative efficacy of selenium nanoparticles (SeNPs) on AlCl3-induced hepatorenal injury in rats. Animals were randomly divided into four groups (n = 6): group 1, the control; group 2, received SeNPs (0.4 mg/kg b.wt) for 21 days; group 3, injected with three doses of AlCl3 intraperitoneally (30 mg/kg/body weight) every 5 days; group 4, received SeNPs for 7 days prior to AlCl3 and then received SeNPs concurrently with AlCl3 for the following 14 days. It was observed that AlCl3 increased the levels of AST, ALT, ALP, LDH, total bilirubin, creatinine, urea, uric acid, and MDA significantly; as well as the reduction in the levels of GSH, SOD, GPx stores in comparison with the control group. These biochemical alterations were accompanied and confirmed by the lesion appeared in histological sections in addition to the increase in the expression of caspase-3 and the decrease of the Bcl-2expression. Treatment with SeNPs ameliorates the hepatorenal dysfunction, replenishes the endogenous antioxidant system, downregulates the expression of caspase-3, and upregulates the expression of Bcl-2. This hepatorenal ameliorative role may be due to the ability of SeNPs to equilibrate the oxidant/antioxidant system besides its ability to attenuate apoptosis process.