Recent attention is focused on the impact of diet on health and mental well-being. High-salt and cholesterol diet (HSCD) is known to be associated with neuroinflammation which is the predominant factor for neurodegenerative disease like Alzheimer disease (AD). In the present study, we examined the neuroprotective potential of rosuvastatin, an HMG-CoA reductase inhibitor against HSCD induced neuroinflammation and cognitive impairment. Our results demonstrated that HSCD-induced cognitive impairment as determined by Morris water maze (MWM) task. HSCD also activated nuclear factor kappaB (NF-kB) signaling pathway. The cytokine response was measured using a cytometric bead-based assay quantified by flow cytometry. Treatment with rosuvastatin decreased the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and increased interleukin-10 (IL-10) in a dose-dependent manner. Our results also demonstrated that the rosuvastatin modulates neuronal cell death by inhibiting the overexpression of NF-kB in the CA1 region of hippocampus. In addition, molecular docking study of rosuvastatin indicated high affinity and tighter binding capacity for the active site of the NF-kB. These results suggest that HSCD-triggered inflammatory response and cognitive impairment may be associated with NF-κB signaling pathway. Therefore, treatment with rosuvastatin could be a potential new therapeutic strategy for sporadic dementia of AD.