This study was constructed to explore the neuroprotective significance of grape seed extract (GSE) in management of neurodeterioration produced by Ethanol (EtOH) inhalation in rats. Fifty adult female rats were enrolled in this study and divided into 5 equal groups. The experimental period lasted 12 weeks, after which nitric oxide (NO), hydrogen peroxide (H2O2), dopamine (DA), adrenaline (AD), noradrenaline (NA), brain derived neurotrofic factor (BDNF), B-cell lymphoma 2 (Bcl-2) levels were assayed in the brain. Additionally, brain Bcl-xl gene expression level was determined using RT-PCR. Immunohistochemical technique was used for assessment of survivinimmunopositive cells intensity in the brain tissue. Furthermore, histopathological investigation of brain tissue was carried out. The results indicated that inhalation of EtOH elicited significant elevation in brain NO, H2O2 and Bcl-2 levels, accompanied with significant depletion in brain DA, AD, NA and BDNF levels. Significant upregulation in brain Bcl-xl gene expression level was also recorded in EtOH-challenged groups. In addition, significant elevation in the intensity of survivinimmunopositive cells in the brain has been detected due to EtOH inhalation. Histological investigation of brain tissue section of rats in EtOH- challenged groups showed pronounced pathological alterations. However, pre-treatment of EtOH challenged groups with grape seed extract resulted in significant improvement in the biochemical, molecular and immunohistochemical parameters. These findings were documented by histological investigation of brain tissue which revealed the ability of grape seed extract to restore the structural organization of the brain. In conclusion, the present study clearly indicated that grape seed extract represented a good neuroprotective candidate against EtOH- induced neuropathy due to its powerful antioxidant activity, anti- apoptotic potential and neurotrophic effect.