The goal of the present study is to assess the possible protective effect of the pomegranate peel extract (PPE) and its alginate-nanoencapsulated form (Alg-PPE NPs) against rat neurotoxicity induced by acrylamide (ACR). The Alg-PPE NPs were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential, Fourier transmission infrared microscopy (FITR), differential scanning calorimetry (DSC) and in vitro cytocompatibility and drug release analysis. ACR was intraperitoneally injected (50 mg/kg bw) three times per week for 2 consecutive weeks into male Wistar rats for the induction of neurotoxicity. PPE or Alg-PPE NPS were given in daily doses (200 mg/kg bw) orally for two consecutive weeks either individually or combined with acrylamide injection. Results revealed that ACR injection induced neurotoxicity manifested by the significant increase in tumor necrosis factor alpha, gamma aminobutyric acid, and DNA fragmentation level in brain tissues of treated animals. Meanwhile, the brain levels of brain-derived neurotrophic factor, total antioxidant capacity, acetylcholinesterase activity, dopamine, serotonin, norepinephrine, glutamine, glycine, and aspartate were significantly decreased. These changes in tissue biochemical parameters were associated with histopathological alternations in the architecture of brain tissues. Amelioration of the acrylamide-induced brain toxicity was observed following co-administration of either PPE or Alg-PPE NPs with a higher degree of protection observed with the nanoparticles form as a result of increased bioavailability. In conclusion, Alg-PPE NPs can be regarded as a potential therapeutic agent that offers protection against acrylamide neurotoxicity, however, to fully understand the neuroprotective mechanism of Alg-PPE NPs, additional research must be done.