Chronic cerebral hypoperfusion is associated with vascular cognitive impairment, and there are no specific therapeutic agents for use in clinical practice. Berberine has demonstrated good neuroprotective effects in models of acute cerebral ischemia; however, whether it can alleviate cognitive impairment caused by chronic cerebral hypoperfusion has rarely been investigated.The present study aimed to explore the mechanism by which berberine alleviates cognitive impairment resulting from chronic cerebral hypoperfusion.Forty-two male Sprague-Dawley rats were randomly divided into three groups: sham, model, and berberine. The models of chronic cerebral hypoperfusion were established via permanent bilateral common carotid artery occlusion (BCCAO). Cognitive function was evaluated using the Morris water maze, while neuronal damage and microglial activation and polarization were evaluated using western blotting and immunofluorescence, respectively. Enzyme-linked immunosorbent assays were used to detect the expression of anti-inflammatory factors including interleukin-4 (IL-4) and interleukin-10 (IL-10).Rats exhibited cognitive dysfunction after BCCAO, which was significantly attenuated following the berberine intervention. Levels of synaptophysin and NeuN were decreased in states of chronic cerebral hypoperfusion, during which microglial activation and a transition from the M2 to M1 phenotype were observed. Berberine treatment also significantly reversed these features. Moreover, levels of IL-4 and IL-10 expression increased significantly after berberine treatment.Berberine may mitigate vascular cognitive dysfunction by promoting neuronal plasticity, inhibiting microglial activation, promoting transformation from an M1 to an M2 phenotype, and increasing levels of IL-4 and IL-10 expression.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.