Acrylamide (Ac) is a carbonyl compound extracted from hydrated acrylonitrile with a significantly high chemical activity. It is widely existed and used in food processing, industrial manufacturing and laboratory personnel work. However, lycopene (Ly) is a most potent natural antioxidant among various common carotenoids extracted from red plants. Nevertheless, little is known about the relationship of Ac-induced neurotoxicity and the ameliorative role of Ly in the regulation of oxidative and antioxidant capacity during Ac exposure. Therefore, this work sought to investigate the neurotoxicity induced by Ac exposure and the potential modulatory role of Ly by reversing the brain dysfunctions during Ac exposure. For this purpose, forty male albino rats were assigned into four equal groups. Control group received distilled water, Ly group was given with a daily dose of 10 mg/kg bw, Ac group was given with a daily dose of 25 mg/kg bw, and Ac-Ly group was gavaged Ac plus Ly at the same doses as the former groups. All treatments were given orally for 21 consecutive days. The concentrations of antioxidants (reduced glutathione and glutathione peroxidase) and oxidative stress (malondialdehyde, nitric oxide and protein carbonyl) biomarkers, as well as neurotransmitters (serotonin and dopamine) and acetylcholinesterase (AChE) were measured in the brain homogenates. An immunohistochemical staining was applied with anti-GFPA antibody to determine the severity of astrocytosis. The in vivo study with rat model demonstrated that Ac exposure significantly decline the hematological parameters, brain neurotransmitters concentrations and AChE activity, as well as levels of antioxidant biomarkers but markedly elevate the levels of oxidative stress biomarkers. Moreover, marked histological alterations and astrocytosis were observed through the increased number of GFAP immunopositively cells in cerebral, cerebellar and hippocampal tissues compared with the other groups. Interestingly, almost all of the previously mentioned parameters were retrieved in Ac-Ly group compared to Ac group. These findings conclusively indicate that Ly oral administration provides adequate protection against the neurotoxic effects of Ac on rat brain tissue function and structure through modulations of oxidative and antioxidant activities.