Cisplatin is a widely used chemotherapeutic agent known to cause dose-dependent neurotoxicity, yet the underlying histopathological and molecular mechanisms remain incompletely understood. This study aimed to investigate the neurotoxic effects of different cisplatin dosing regimens on rat brain tissue and to evaluate associated molecular responses, including Tumor necrosis factor-alpha, Heat Shock Protein 70, Brain natriuretic peptide, and Hypoxia-inducible factor 1 alpha expression. Thirty-eight male Wistar albino rats were randomly assigned to five groups: control, single-dose cisplatin (4 mg·kg–1 and 8 mg·kg–1), and split-dose cisplatin (2×2 mg·kg–1 and 2×4 mg·kg–1). Following administration, brain tissues were collected for histopathological evaluation and quantitative real-time Polymerase Chain Reaction analysis. Histopathological assessments revealed dose-dependent neuronal necrosis, gliosis, perivascular edema, neuronophagia, and congestion, with the most severe alterations observed in the single 8 mg·kg–1 dose group. Split-dose regimens elicited milder changes, suggesting that peak plasma concentrations may drive acute neurotoxicity. Molecular analyses demonstrated concurrent upregulation of tumor necrosis factor-alpha and heat shock Protein 70 messenger ribonucleic acid, indicative of an endogenous protective response against cisplatin-induced neuroinflammation. Notably, brain natriuretic peptide and hypoxia-inducible factor 1 alpha levels exhibited increasing trends across all cisplatin – induced groups; these molecules have not previously been investigated in the context of cisplatin-induced neurotoxicity, highlighting a novel aspect of potential adaptive responses. The results indicate that cisplatin neurotoxicity is dose-dependent and more pronounced with high single doses, while split-dose administration may allow partial activation of protective mechanisms, mitigating histopathological damage. Collectively, these findings advance the understanding of cisplatin-induced brain injury, underscore the significance of dosing strategies in minimizing neurotoxic risk, and provide new insights into molecular pathways that may contribute to adaptive responses and neuroprotection.