Mesenchymal stem cells (MSCs) possess a preventive capacity against free radical toxicity in various tissues. The present study aimed to demonstrate the reformative and treatment roles of adipose-derived MSCs (AD-MSCs) against severe toxicity in the hippocampal cells of the brain caused by aluminum oxide nanoparticles (Al₂O₃-NPs). Rats were divided into five experimental groups: an untreated control group, a control group receiving NaCl, a group receiving Al₂O₃-NPs (6 mg/kg) for 20 days, a group that was allowed to recover (R) for 20 days following treatment with Al₂O₃-NPs, and a Al₂O₃-NPs + AD-MSCs group, where each rat was injected with 0.8 × 10⁶ AD-MSCs via the caudal vein. Oral administration of Al₂O₃-NPs increased the protein levels of P53, cleaved caspase-3, CYP2E1, and beta-amyloid (Aβ); contrarily, AD-MSCs transplantation downregulated the levels of these proteins. In addition, the AD-MSCs-treated hippocampal cells were protected from Al₂O₃-NPs-induced toxicity, as detected by the expression levels of Sox2 and Oct4 that are essential for the maintenance of self-renewal. It was also found that AD-MSCs injection significantly altered the levels of brain total peroxide and monoamine oxidase (MAO)-A and MAO-B activities. Histologically, our results indicated that AD-MSCs alleviated the severe damage in the hippocampal cells induced by Al₂O₃-NPs. Moreover, the role of AD-MSCs in reducing hippocampal cell death was reinforced by the regulation of P53, cleaved caspase-3, Aβ, and CYP2E1 proteins, as well as by the regulation of SOX2 and OCT4 levels and MAO-A and MAO-B activities.