This study was aimed at evaluating the protective effect of sodium selenite (SS) on DNA integrity, antioxidant/oxidant status, and histological changes on 4-nonylphenol (4-NP)-induced toxicity in liver and kidney tissues of rats. Twenty-four adult male Sprague Dawley rats were divided into 4 groups as control, SS, 4-NP, and SS+4-NP group. Control group was untreated. The SS group was supplemented with SS (0.5 mg/kg/day) and the 4-NP group was given 4-NP (125 mg/kg/day). The rats in the SS+4-NP group received SS followed by 4-NP 1 h later at the abovementioned doses. The treatments were administered by oral gavage for 48 days. DNA damage was analyzed by comet assay in lymphocytes. Oxidative stress parameters were measured, and histological evaluation was performed in liver and kidney tissues. Results showed that SS administration significantly decreased % Tail DNA and Mean Tail Moment in SS+4-NP group as compared with 4-NP group. Catalase activity in liver was significantly lower in 4-NP group only. SS treatment significantly increased the glutathione level and decreased high malondialdehyde level in tissues of the SS+4-NP group as compared with 4-NP group. Dilation of central vein, ballooning degeneration, vacuolar degeneration, and deterioration in the structure of remark cords in 4-NP-administered were alleviated in rats that received SS supplementation before administration of 4-NP. Moreover, glycogen intensity in hepatocytes and the wall of central vein increased in the SS+4-NP group. In addition, the SS supplementation in the SS+4-NP group decreased glomerular degeneration as well as the width of cavum glomeruli and congestion intensity in the kidney. These results indicate that SS may have a protective effect against 4-NP-induced hepato-nephrotoxicity in rats.