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AIM: To investigate the therapeutic effects of syringin (SY) on vascular cognitive impairment (VCI) in rats and its possible mechanisms. METHODS: The rats were allocated into three groups: sham group(n=15); model group (n=21); and SY treatment group (n=19). The VCI rat model was induced via a modified bilateral ligation of the common carotid artery. Three days after the model induction, the SY treatment group received intraperitoneal injections of 50 mg/kg SY once daily for 28 d. In total, 15 rats in the sham operation group, 17 rats in the model group, and 17 rats in the SY treatment group were included for further investigation. The cognitive and learning functions of the rats were assessed using the Morris water maze test, Y-maze test, and novel object recognition experiment. Cerebral blood flow was monitored through laser speckle imaging, while Evans blue staining was used to assess damage to the blood-brain barrier. Nissl staining, microtubule-associated protein-2(MAP-2), and neuronal nuclear antigen(NeuN) co-localization immunofluorescence staining demonstrated the extent of hippocampal damage. ELISA was employed to measure the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in the brain tissue. Microglial activation was observed viaionized calcium-binding adapter molecule 1 (IBA1) immunofluorescence staining, and Western blot analysis detected the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and phosphorylated (p)-P65 proteins in the brain tissue. RESULTS: Compared with the sham group, rats in the model group exhibited reduced cognitive function and cerebral blood flow (P<0. 01), increased blood-brain barrier permeability and degree of hippocampal tissue damage (P<0. 01), upregulation of TLR4, MyD88, and p-P65 protein expression in the brain tissue (P<0. 01), elevated levels of IL-1β, IL-6 and TNF-α (P<0. 01), as well as microglia activation (P<0. 01). In contrast to the model group, rats in the SY group demonstrated enhanced cognitive function and cerebral blood flow (P<0. 01), decreased blood-brain barrier permeability and degree of hippocampal tissue damage (P<0. 01), downregulation of TLR4, MyD88 and p-P65 protein expression in the brain tissue(P<0. 01), reduced levels of IL-1β, IL-6 and TNF-α, and reduced microglia density (P<0. 01). CONCLUSION: SY enhances cognitive function in VCI rats by improving cerebral blood flow, safeguarding the integrity of the blood-brain barrier, attenuating neuroinflammation, mitigating neuronal damage within the hippocampus, and inhibiting TLR4/MyD88/NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]