BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a significant contributor to vascular cognitive impairment (VCI), often linked to cortical and hippocampal damage. This study investigates the therapeutic potential of salidroside (SLDS) in mitigating CCH-induced brain injury by modulating microglial activation and inflammatory responses. METHODS: We established a CCH model in mice using the 0.16/0.18 mm bilateral common carotid artery stenosis (BCAS) procedure. We assessed cerebral blood flow (CBF) via laser speckle contrast imaging, while neuropathology was evaluated through Nissl staining and immunofluorescence (IF) experiments. Cognitive deficits were measured using the Morris water maze test. Neuronal apoptosis and neuroinflammation were examined through IF, ELISA, and qRT-PCR. RESULTS: BCAS-induced hypoperfusion resulted in a marked reduction in CBF, increased neuronal apoptosis, and significant cognitive deficits. SLDS treatment effectively countered these effects by shifting microglial polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, reducing pro-inflammatory cytokine levels, and enhancing neuronal survival. CONCLUSION: SLDS demonstrates strong neuroprotective potential against CCH-induced brain injury by reducing inflammation and preventing neuronal apoptosis. These findings highlight the promise of SLDS as a therapeutic agent for chronic cerebrovascular disorders, warranting further investigation into its molecular mechanisms and clinical applicability.