Objective <p>The present study intended to demonstrate that chronic administration of cadmium chloride (CdCl₂) causes neurotoxicity in rodents. This research was intended to investigate whether the prolonged Cd administration in experimental Wistar rats may promote behavioral alterations, demyelination of axons, mitochondrial dysfunction, free-radical-mediated oxidative stress, neuroinflammation, neuronal apoptosis, followed by neuronal death.</p> Methodology <p>In this study, rats were administered CdCl₂ (2 and 4&#xa0;mg/kg) orally for a consecutive 28&#xa0;days. Morris water maze, elevated plus maze, narrow beam walk apparatus, and rota-rod were used to assess the working memory deficits and neuromotor performance. On the 29th day, the rats were sacrificed after euthanasia, and all their brains were used for assessing biochemicals, neuroinflammation, BBB integrity, mitochondrial respiratory chain, neurotransmitters, calcium homeostasis, apoptotic markers, and molecular markers alteration.</p> Results <p>CdCl₂ administration altered working and spatial memory formation, depletion of oxidant and antioxidant homeostasis, alteration in mitochondrial functions, neurotransmitter levels, and elevated cytokine production, apoptosis in the corpus callosum (CC) in a dose-dependent manner. It possesses a detrimental effect on myelin basic protein production and thus affects the axonal myelination process in the brain, a major pathological marker of MS. The histological and immunohistochemistry analysis highlighted that CdCl₂-induced neurodegeneration and activated transcriptional factors, including nuclear factor-κB (NF-κB) and nuclear&#xa0;factor&#xa0;erythroid 2-related factor&#xa0;2 (Nrf2), in the CC region.</p> Conclusion <p>The outcomes of this study suggested that prolonged CdCl₂ administration induced significant alterations in behavioral, biochemical, myelination, neuroinflammatory, histopathological parameters, and neurodegeneration following low to high-dose administration.</p>