The present study investigated the effect of the various fractions of hydromethanolic extract of the leaves of Vitex negundo (Verbenaceae) against ethanol-induced cerebral oxidative stress in rats. Cerebral oxidative stress was induced by the administration of 20% ethanol (5 ml/100gbw) for a period of 28 days. The petroleum ether (PEF), chloroform (CF), ethylacetate (EAF) and residual (RF) fractions at a dose of 200 mg/kgbw orally were simultaneously administered with ethanol for 28 days. α-tocopherol at a dose of 100 mg/kg orally was used as the standard. Administration of ethanol resulted in a significant elevation in serum biochemical parameters like aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), uric acid, triglycerides and lipoprotein levels. In addition there was a significant (P<0.01) elevation in malondialdehyde (MDA) and lipid hydroperoxide (LH) levels and a significant (P<0.01) reduction in enzymatic and non-enzymatic antioxidants in the brain tissue. Histopathological examination of the brain tissue of the ethanol treated animals showed marked gliosis. Simultaneous administration of the fractions prevented the enzymatic leakage and elevation of serum uric acid, triglycerides and lipoprotein levels. All the fractions (except the residual fraction) prevented the rise in lipid peroxidation and enhanced the antioxidant enzymes. Further, histopathological examination revealed that the fractions of V. negundo offered a significant protection against ethanol toxicity in rat brain. The activity exhibited by the chloroform fraction is comparable to that of the standard. The present study reveals that the leaf of V. negundo has protective action on the brain, which could be attributed to its antioxidant potential. __________________________________________________________________________________________