Valproic acid (VPA) is an effective drug, which is preferred for the treatments of epilepsy and various kinds of seizures. Nonetheless, VPA has many life-threatening side effects associated with free radical production. Alpha-lipoic acid (ALA) is a powerful antioxidant, which can scavenge reactive oxygen species (ROS). The effects of ALA against VPA-stimulated brain injury were investigated. In this study, Sprague-Dawley rats were divided as four groups: Group I, control rats; Group II, ALA-administered rats (50 mg/kg/d); Group III, VPA-administered rats (0.5 g/kg/d); Group IV: VPA- and ALA-administered rats at the same dose and time. According to the results, VPA increased lipid peroxidation, protein carbonyl, advanced oxidation protein products, total oxidant status, nitric oxide levels and glutathione-S-transferase, adenosine deaminase, xanthine oxidase activities, decreased glutathione, total antioxidant capacity levels, catalase, superoxide dismutase, glutathione peroxidase, sodium-potassium ATPase, and paraoxonase activities. Treatment with ALA reversed these effects. In conclusion, we may suggest that ALA may be a good candidate for prevention of VPA-induced brain injury.