<p>Vascular dementia (VaD) is driven by chronic cerebral hypoperfusion and neuroinflammation, yet effective interventions capable of acting on multiple pathological processes remain limited. Danzhu Fuyuan Granules (DFG) has been used clinically for cognitive impairment, but its therapeutic mechanisms remain poorly elaborated. Bilateral carotid artery stenosis (BCAS)-induced VaD was validated by behavioral evaluation, with cerebral blood flow (CBF), regional homogeneity (ReHo), and fractional anisotropy (FA) assessed by magnetic resonance imaging (MRI), and neuronal and white matter damage examined by histological staining. Serum constituents of DFG were identified using UHPLC-Q-TOF-MS, and potential therapeutic mechanisms were predicted through network pharmacology. RT-PCR, molecular docking, western blotting (WB), and ELISA were used to identify the potential targets. DFG significantly ameliorated cognitive impairment in mice with VaD. MRI showed restored CBF and enhanced ReHo, consistent with histological evidence that DFG attenuated neuronal loss and white-matter damage. Forty serum constituents and 54 putative targets were identified, with 10 core proteins highlighted by network analysis. RT-PCR validated 22 genes linked to angiogenesis, inflammation, oxidative stress, and apoptosis. Molecular docking suggested strong binding of key constituents to hub targets such as KDR and SRC. DFG also restored VEGF family expression and suppressed inflammatory mediators. DFG could improve cognitive function and attenuate neuronal loss and white matter lesions in VaD, potentially by influencing VEGF-related blood flow regulation and anti-inflammation.</p> Graphical Abstract <p></p>