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Titanium dioxide nanoparticles were widely used in food as dietary supplements, in drugs, in toothpaste, ect. Few numbers of studies were interested to the neurotoxicity of TiO 2 NPs through oral pathway. The present study aims firstly to understand the connection between the physicochemical properties of TiO 2 NPs and their associated toxicological oral pathway by evaluation the colloidal stability of TiO 2 NPs over time in different media simulating physiological gastric, intestinal and serum conditions at 37 °C to be close to the oral administraton. Secondly, this study aims to evaluate the neurotoxicity of a subchronic intragastric administration of TiO 2 NPs to rats. Different doses of anatase TiO 2 NPs were administrated to Wistar rats every day for consecutives eight weeks. Titanium (Ti) content in brain, oxidative antioxidant biomarkers, lipid peroxidation, nitric oxide (NO) levels, tumor necrosis factor-alpha (TNF-α) levels, histophatological changes, degenerated and apoptosis neurons were investigated. Results suggested that TiO 2 NPs can reach the brain and cross the brain blood barrier (BBB) to been accumulated in the brain of rats causing cerebral oxidative stress damage, increasing NO levels and histopathological injury. At higher dose, we observed the most cerebral injury by the highest accumulation of Ti and by the remarkable increase of TNF-α besides to the most increase of degenerated and apoptosis neurons in the brain of exposed rats. TiO 2 NPs led to a neurotoxic damage accompanied by the increase of degenerated and apoptotic neurons in cerebral cortex., (Copyright © 2019. Published by Elsevier Inc.)