Neuroinflammation plays a central role in neurodegenerative diseases, with lipopolysaccharide (LPS) serving as a widely used experimental model for inducing neurotoxicity. This study investigates the modulation of nitric oxide (NO) and interleukin-6 (IL-6) in LPS-induced neurotoxicity using wistar rat models. 20 Wistar rat models weighing 150 - 180g were used and randomly assigned into four groups: Group 1 (Control), Group 2 (Low dose LPS - 0.25mg/kg), Group 3 (Medium dose LPS - 0.5mg/kg), Group 4 (High dose LPS - 1.0mg/kg). LPS was administered intraperitoneally, and neuroinflammatory markers were quantified using biochemical assays. Neurobehavioral activities (Navigation test, Object Recognition, and Barnes maze test) were recorded and analyzed using ANOVA. Results showed that NO and IL-6 levels increased in a dose- dependent manner following LPS exposure. The High-dose LPS group exhibited the highest levels of NO and IL-6, correlating with significant neuronal damage in the hippocampus. Elevated NO production suggests oxidative stress-mediated neurotoxicity, while increased IL-6 levels indicate an amplified inflammatory response contributing to synaptic dysfunction. Histopathological analysis revealed neurodegeneration, particularly in the hippocampal CA1 and CA3 regions, further supporting the role of inflammation in cognitive impairment. These findings highlight the interplay between NO and IL-6 in LPS-induced neurotoxicity and suggest that targeting these pathways could offer therapeutic potential for neuroinflammatory disorders, including Alzheimer’s disease and Parkinson’s disease. Understanding how these inflammatory mediators contribute to cognitive dysfunction may lead to novel strategies to mitigate neurodegeneration and improve cognitive outcomes in neuroinflammatory conditions.