Cisplatin (CP) has improved cancer patients' survival rates. However, it is associated with both peripheral and central neurotoxicity. Nigella sativa oil (NSO) possesses anti-inflammatory, anti-tumor, antimicrobial, and antioxidant properties. This work addresses CP-based cognitive impairment and central neurotoxicity, offering an all-encompassing perspective on NSO as an eventual protective drug and its CNS neuroprotection processes. Three groups were employed: the control rats, the CP-treated group, and the NSO+CP-treated group. CP induced substantial neurotoxicity, including cognitive impairments, increased depressive-like behaviors, anxiety-like behaviors, and impaired memory performance. In addition, the oxidative distress triggered by CP increased the generation of malondialdehyde (MDA). It decreased the levels of glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, as well as nuclear factor erythroid 2-related factor 2 (Nrf-2) mRNA expression. Moreover, increased cellular content of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), caspase-3, BAX/BCL2 ratio, IL-6 mRNA expression, caspase-3 mRNA, NLRP3 mRNA expression, and protein expressions indicated the occurrence of inflammatory changes and cell apoptosis. The findings revealed that NSO supplementation helped mitigate these toxic changes induced by CP due to its antioxidant and anti-inflammatory properties. They are mediated, at least in part, by enhancing the Nrf2/HO-1 pathway and hindering the NLRP3 inflammasome. This molecular modification was directly correlated with behavioral enhancement, providing new mechanistic understanding into the therapeutic potential of NSO.