Lead acetate (lead ac.) is a widespread ecological toxicant that can cause marked neurotoxicity and decline in brain functions. This study aimed to evaluate the possible neuroprotective role of L-ascorbic (ASCR) and curcumin (CRCM) alone or together against lead ac.-induced neurotoxicity. Rats were injected with lead ac. then treated orally with ASCR and CRCM alone or in combination for seven days. Lead ac. caused elevation in brain tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), caspase-3, and malondialdehyde (MDA) levels, while superoxide dismutase (SOD), reduced glutathione (GSH) as well as the expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding (CREB) and Beclin1 were down-regulated. Expressions of C/EBP homologous protein (CHOP) and mammalian Target of rapamycin kinase (mTOR) were upregulated in brain tissues matched with the control group. Histopathological examination supported the previously mentioned parameters, the administration of the antioxidants in question modulated all the altered previous parameters. The combination regimen achieved the superlative results in the antagonizing lead ac.-induced neurotoxicity via its antioxidant and anti-apoptotic activities.