High cholesterol diet was responsible for metabolic disease development that considers one of the public health problems. However, there is a little information about the impact of barley supplementation on hypercholesterolemia associated cerebral damage. Sixty virgin female albino rats (Rattus norvegicus) weighing 100 g body weight were used and categorized into four groups (control, barley, a hypercholesterolemic diet with/without barley). The hypercholesterolemic females ingested a high cholesterol diet (3% cholesterol) for four months before conception and throughout gestation and lactation period. Dams of the studied groups were sacrificed at the third week-postpartum. Cerebrum was removed and processed for histopathological, proliferating cell nuclear antigen (PCNA) and glial fibrillary acidic protein (GFAP) immunohistochemical investigations. Assessments of antioxidants, lipid peroxidation, neurotransmitters and interleukins levels were carried out. The present findings showed that the ingestion of drenched barley to mothers fed on a high cholesterol diet decreased lipid peroxidation, and decreased inflammatory markers coincides with increased assayed both antioxidant enzymes and neurotransmitters. These were reflected in the histological picture as well as increased proliferating cell nuclear antigen and decreased glial fibrillary acidic protein immunohistochemically. The authors concluded that drenched barley contains essential nutrients and flavonoids which increased the antioxidant defense facilitated to improve the drastic damage induced by a high cholesterol diet on cerebral neurons and restored their functional activity.