Background: Toluene is a chemical hydrocarbon that affects mainly the central nervous system. Resveratrol has a large spectrum of beneficial health effect. Aim: The study aimed to assess the protective effect of Resveratrol (RES) on cerebrum injury in rat caused by toluene (TN). Materials and Methods: Thirty adult male Wistar albino rats were used in this study, each weighting 200-250 g, aging 4-6 months. They were separated into five equal groups, Control group: The animals had only regular diet and tap water, Corn oil group: was given 0.1 ml/10 g/day corn oil, intraperitoneally, TN-treated group: The animals received Toluene intraperitoneally with a dosage of 500 mg/kg/day (n ¼ 7) (0.1 g/ml, in corn oil) (0.5ml/kg/day) for 14 days, RES group: The animals received resveratrol 10 mg/kg/day intraperitoneally for 14 days, and TN+RES treated group: The animals received toluene alongside supplemented with resveratrol (as previous doses) for 14 days. All rats were anesthetized, scarified and the brain was dissected out. Parts of brain tissues were processed for tissue homogenates for measuring MDA, SOD, Gpx. A nd other parts of the brain tissues were subjected to histopathological examination (light and electron microscopic examination). Immunohistochemical staining for BCL2, BAX, GFAP and synaptophysin were performed with morphometric and statistical analysis. Results: Toluene revealed increment in MDA together with a decrement of SOD and Gpx activity. Moreover, Toluene exhibited obvious histopathological deterioration with over expression of Bax protein and glial fibrillary acidic protein (GFAP) and down expression of Bcl2and synaptophysin. RES restored the biochemical profile of oxidative damage and improved the histopathological and immunohistochemical picture. Conclusion: In conclusion, our results speckled a bright on the probable effective role of RES on cerebrum injury induced by toluene and provide available suggestion on the potential clinical effectiveness of RES supplementation in case of cerebrum injury.