This study aimed to investigate the possible beneficial effects of grape seed oil (GSO) on CCl₄-induced acute brain toxicity in rats. The animals injected with acute dose of CCl₄ (2 ml / kg b. wt.) showed a statistical significant decrease in the blood hematological parameters (WBCs, RBCs, PLT counts, Hb and MCV values), and a significant elevation in serum TNF-α, and IL-6 levels. In addition, damage of the brain DNA, disturbance of the brain antioxidant status; a significant decrease in SOD, GSH-Px and Catalase (CAT) activities as well as GSH level, accompanied with a significant elevation in MDA and NO levels, as well as a high significant elevation in xanthine oxidase and inducible nitric oxide synthase (iNOS) gene expressions have been observed due to the oxidative stress produced after CCl₄ injection. The pretreatment of GSO exert significant ameliorated the hematologic parameters, and serum TNF-α and IL-6 levels,  protected DNA damage, improved SOD, GSH-Px and CAT activities as well as GSH, MDA and NO levels and down-regulation of  xanthine oxidase (XO) and inducible nitric oxide synthase (iNOS)gene expression levels in the brain tissues of CCl₄ injected rats. These findings suggest that GSO prevents acute brain damage due to CCl₄ toxicity, which could be attributed to its immuno-modulation and antithrombotic, antiapototic, antioxidant, and anti-inflammatory activities. It can be suggested that GSO which containing high level of polyphenolic compounds, essential fatty acids and vitamin E (Tocopherol) revealed to protect the brain from CCl₄ toxicity and/or any other toxicant cause oxidative stress.