Background: Lead (Pb) and aluminum (Al) are ubiquitous environmental pollutants and are known to induce neurodegenerative disorders. They enhance neuronal changes and may involve glial alterations and other consequences. We intend to evaluate the mechanism through which the long-term exposure to Pb acetate alone or in combination with aluminum-chloride induced neurological impacts in rats. Methods: For this aim, a total number of forty male Sprague Dawley rats were assigned into four groups. Control (DW), Pb acetate (12.5 mg/kg BW), Al chloride (64 mg/kg BW), and the combination group were experimentally exposed for 60 days. Biochemical evaluation of oxidative stress biomarkers, transcriptional-mediated changes in the expression pattern of OGG1 and P53 genes by qRT-PCR were applied. Histopathological modifications in the brain tissue with immunohistochemical reactivity of GFAP were also detected. Results: Our findings revealed that lipid peroxidation was markedly enhanced but inhibited antioxidant enzyme activity in brain tissue in all exposed groups regarding the control. Pb-acetate elevated the biochemical concentration of dopamine and serotonin while AlCl3 declined their levels in the brain homogenate of rats. Furthermore, the exposure to one or both metals elevated the comet assay indices and serum level of 8-hydroxy- 2′ –deoxyguanosine, up-regulated the expression of P53, OGG1 and GFAP immunoreactivity in the central nervous system. Histologically, they caused several brain tissue alterations. Conclusion: The exposure to Pb and/or Al could be key candidates for neurodegenerative changes in the brain of rats via oxidative, apoptotic, and DNA damaging pathways. Besides, according to our findings, exposure to both Pb acetate and Aluminium chloride have synergistic damaging effects on the central nervous system of rats. Also, they have opposing effects on the secretion of monoamine neurotransmitters DA and 5 H T.