Hyperlipidemia describes abnormally high levels of lipoproteins, cholesterol, triglycerides in the blood. It is contributed by high fat diet (HFD) rich in saturated fatty acids, sedentary lifestyle plus other factors. HFD induces biochemical alteration associated with structural changes in the frontal cerebral cortex and the cerebellum of rats. This study evaluated the possible protective effect of Nigella sativa (NS) seeds powder on the biochemical and histopathological changes induced by HFD in rat’s cerebellar cortex. It lasts 2 months and involved 24 rats separated into group I, control, group II, fed with HFD (20gm/100gm of diet/day), group III, fed with HFD plus treated with NS seeds powder (300mg/kg/day). After treatment, blood samples were collected for lipid profile assessment. Cerebelli were extracted and processed for histological examination. Body weight was increased in the hyperlipidemic group compared with the control group but reduced again by NS treatment. The serum lipid profile in hyperlipidemic rats showed significant improvement in rats fed on HFD with NS seeds powder. Microscopically, the cerebellar cortex of hyperlipidemic group showed marked degenerative changes in Purkinje cell layer with many swollen Bergmann cells. GFAP expression was abundant in the astrocytes of the three cortical layers. The cerebellar cortex of hyperlipidemia with NS-treated group showed marked improvement as most of the Purkinje cells had almost normal appearance and GFAP expression showed moderate expression as the control group. This study revealed significant biochemical results that are compatible to the histological and immunohistochemical findings. Thus, NS seeds had neuroprotective effects from hyperlipidemia-induced injury in the cerebellum.