The primary objective of this study was to investigate the adverse effects of Bisphenol-A (BPA) on the central and peripheral nervous systems at molecular, histopathological, and immunohistochemical levels, as well as to evaluate the potential neuroprotective effects of Nigella Sativa seed oil (NSO). Rats were administered BPA at a dosage of 100 mg/kg body weight per day via gavage for 30 days, alongside NSO at a dosage of 5 ml/kg body weight per day for the same duration. Rats were sacrificed 24 h after the final administration, and molecular, histopathological, and immunohistochemical examinations were conducted on brain and sciatic nerve tissues. BPA exposure resulted in neurotoxic effects in both the central nervous system (brain) and peripheral nervous system (sciatic nerve), leading to oxidative stress, apoptosis, and neurodegeneration. Specifically, glutathione (GSH) levels decreased, while malondialdehyde (MDA) levels increased in both tissues due to BPA administration. Additionally, BPA elevated the gene expression levels of nuclear factor erythroid 2–related factor 2 (Nrf2), Caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA transcripts, while decreasing the expression of nuclear receptor subfamily 4 group A member 2 (NR4A2). In contrast, NSO administration alongside BPA increased GSH content in both tissues and significantly reduced MDA levels. Moreover, NSO decreased the gene expression levels of Nrf2, NF-κB, and Caspase-3 mRNA transcripts, while increasing NR4A2 expression. Furthermore, the neurodegenerative manifestations induced by BPA—such as neuronal degeneration, necrosis, neuronophagy, hemorrhage, gliosis, and elevated glial fibrillary acidic protein (GFAP) levels in the brain—were mitigated by the concurrent administration of NSO, indicating its neuroprotective efficacy. In conclusion, this study provides promising evidence that NSO may therapeutically alleviate BPA-induced neurodegeneration.