Abstract: Chromium is considered as a potential environmental toxin depending on its valence state. The intracellular metabolism of hexavalent chromium or chromium VI leads to oxidative stress. This study aims to determine the potential effect of avocado (Persea americana Mill) seed extract (ASE) against neurotoxicity induced by chromium VI in male New Zealand white rabbits. Three different groups were formed, each containing five rabbits; Group one was kept as control (G1). The next group (GII) was intraperitoneally injected by a dose (5 mg/Kg) of potassium dichromate Cr (VI) / day for two weeks. The third group (GIII) was intraperitoneally injected by a daily dose (5 mg/Kg) of Cr (VI) concurrently with an oral dose of ASE (400 mg/kg) for two weeks. Brain homogntes and serum of Cr (VI)-treated rabbits showed a remarkable elevation (P<0.05) in the case of lipid peroxidation, along with concomitant decline in glutathione (GSH) content as well as the activity and gene expressions of the antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Persea americana seed extract enhanced the activities and gene expressions of antioxidant enzymes when administered along with Cr (VI). In addition, the histopathological and immunohistochemical findings of the cerebral cortex of Cr (VI) group showed a significant degeneration of neurocytes with an elevation in the astrocytes that were positive for Glial fibrillary acidic protein (GFAP) and a visible increase in the apoptotic cells. These histological and immunohistochemical alterations were normalized by co-adminstartion of ASE. In conclusion, ASE enhances the antioxidant effects and anti-inflammatory defense mechanisms to protect brain tissues against toxicity induced by Cr (VI).