Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood-brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.Copyright © 2022. Published by Elsevier B.V.