To investigate the mechanism underlying the effects of Fostamatinib on NLRP3 in microglia within vascular dementia (VaD). Methods: ① A bilateral common carotid artery stenosis (BCAS) mouse model was established. The cognitive impairment in mice was validated through the eight-arm maze behavioral test. Sham-operated (Sham) group, as well as multiple time points at 3 days, 1 month, and 3 months after BCAS surgery, were set up. Immunofluorescence staining and Luxol fast blue (LFB) staining were employed to evaluate the activation of microglia and the extent of white matter damage. The time point with the most pronounced damage was selected as the model establishment group. ② Control group, BCAS model group, and (BCAS + fostamatinib treatment) group were established. Immunofluorescence staining and LFB staining were utilized to investigate the effects of fostamatinib on microglia activation, white matter damage, cognitive dysfunction, and the expression of related inflammatory factors in BCAS mice. ③ An ex vivo primary microglia model with exogenous myelin stimulation was established. The cells were treated with fostamatinib or siRNA. Western blot and real-time fluorescence quantitative PCR techniques were used to detect changes in the expression of key proteins and genes in the inflammatory pathway. Results: ① Compared with the control group, the mice in the model group exhibited impaired memory function at 1 month after BCAS surgery, with the highest white matter damage score on LFB staining and the most significant reduction in the fluorescence intensity of myelin basic protein (MBP). Sholl analysis revealed the most pronounced activation of microglia. ② Compared with the model group, the fostamatinib treatment group showed improved reference memory in mice, a reduced white matter damage score, and decreased microglia activation according to Sholl analysis. Immunofluorescence staining demonstrated a significant decrease in the expression of the pro-inflammatory factors NLRP3 and SYK (P<0.05). ③ In vitro, fostamatinib treatment significantly reduced the expression of inflammatory-related factors such as NLRP3, SYK, ASC, Caspase-1, and IL-18 in microglia after myelin treatment (P<0.05). Consistent with these findings, knocking down SYK using siRNA also resulted in downregulated expression of inflammatory factors (P<0.05). Conclusion: Fostamatinib may improve the activation of the NLRP3 inflammasome inflammatory pathway in microglia by inhibiting SYK, thereby reducing neuroinflammatory responses, alleviating myelin damage, promoting structural reconstruction after cerebral white matter ischemia, and facilitating the recovery of cognitive function.