The present study was carried to evaluate the cytoprotective effects of N-acetyl cysteine (NAC) and silymarin against sodium arsenate toxicity (NaAsO2) induced oxidative stress in rats. Seventy five male albino rats were divided into five main equal groups of 15 rats each. Group I (control normal group): administered distilled water. Group II (sodium arsenate exposed group): received 1/20th of LD50 of sodium arsenate orally (41 mg/kg body weight/day) over a period of 8 weeks. Group III (sodium arsenate + NAC treated group): received sodium arsenate (41 mg/kg body weight) and treated daily with NAC (200 mg/kg body weight / orally ). Group IV( sodium arsenate + silymarin treated group): received sodium arsenate (41 mg/kg body weight) and treated daily with silymarin (200 mg/kg body weight). Group V( sodium arsenate +NAC+ silymarin treated group): received sodium arsenate (41 mg/kg body weight) and treated daily with NAC(200 mg/kg body weight) and silymarin (200 mg/kg body weight). The obtained results revealed that, a significant increase in serum liver markers enzymes(ALP, GGT, ALT and AST) activities, total bilirubin, IL-6, TNF-α and hepatic tissue L-MDA concentrations with marked decrease in serum total protein, albumin levels and antioxidant enzymes(SOD, CAT and GPx) activities in hepatic tissue were observed in sodium arsenate intoxicated rats. Also, various pathological changes in hepatic and renal tissues were observed in arsenate induced toxicity in rats. Interestingly, the severity of these alterations was reduced after administration of NAC and or silymarin, that exhibited a significant change in all mentioned parameters with best results in combined group. It could be concluded that, NAC and silymarin have a protective antioxidant and anti-inflammatory effects and could be applicable as cytoprotective against oxidative stress of tissue damage mediated by Arsenic intoxication.