Sodium valproate (VPA) used in epilepsy and has hepatotoxic effect in mammals. This work is to assess the role of L-arginin and omega-3 fatty acid against VPA oxidative stress on liver. This study was carried out on 70 rats divided into 7 groups each of 10 rats treated orally once daily 6days/ week; Group I (control), Group II ( L-arginin): each rat was received 300 mg/kg L-arginin, Group III (omega-3): each rat received 300 mg/kg omega-3, Group IV (VIA): Each rat received 400 mg/kg VPA. Group V (VPA and L-arginin): Each rat received the previous doses. Group VI (VPA and omega-3): as before. Group VII (VPA, L-arginin and omega-3 group): as before. There was a significant increase in the mean values of AST, ALT, ALP and TBL in VPA treated group. Upon supplementation with L-arginin or omega-3 to VPA treated rats there was a significant decrease in the mean values of AST, ALT, ALP and TBL. Microscopic examination of liver section of VPA treated rat revealed vacuolated hepatocytes, focal necrosis, and enlarged portal tract. VPA toxicity induced severe liver damage in rats, and administration of either L-arginin or omega-3 protecting liver tissues.