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ObjectiveVascular dementia is the second most common cause of cognitive impairment in older adults, yet effective pharmacological treatments remain limited. Agnuside, a naturally occurring compound with antioxidant and anti-inflammatory properties, has shown vascular-protective potential; however, its role in vascular dementia remains unclear.MethodsA mouse model of permanent bilateral common carotid artery occlusion was established to evaluate the effects of Agnuside. Cognitive function was assessed using the Morris water maze. Cerebral blood flow, tissue injury, and hippocampal cornu ammonis 1 neuronal apoptosis were evaluated using laser speckle imaging, triphenyltetrazolium chloride staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick-end labeling. Transcriptomic and pathway enrichment analyses were performed, and key targets were validated using quantitative real-time polymerase chain reaction and Western blotting.ResultsAgnuside improved spatial learning and memory, increased cerebral blood flow, reduced histopathological damage, and decreased neuronal apoptosis. Angiogenesis-related genes (Mmp3, IL1RN, and ALAS2) were differentially expressed, and selected genes were validated using quantitative real-time polymerase chain reaction. The PI3K-AKT and MAPK pathways were significantly enriched, and Agnuside restored AKT and ERK1/2 phosphorylation.ConclusionsAgnuside exerts neurovascular protective effects in mice with vascular dementia, likely through modulation of angiogenesis-related genes and activation of AKT/ERK signaling. These findings provide evidence that Agnuside serves as a potential therapeutic candidate for vascular dementia.