Objective To investigate the neuroprotective effect and action mechanism of Siwu Decoction in rats with vascular dementia (VD). Methods Adult male Sprague- Dawley rats were randomly divided into sham- operation group, model group, high- and low- dose Siwu Decoction groups (40 and 20 g/kg), and nimodipine group (20 mg/kg), with 12 rats in each group. A rat model of VD was established through middle cerebral artery occlusion/reperfusion. After operation, these groups received respective treatments for 14 d. Their spatial learning and memory abilities were assessed using the Morris water maze. The levels of acetylcholinesterase (AChE), 5- hydroxytryptamine (5- HT), endothelin- 1 (ET- 1), and vascular endothelial growth factor (VEGF) in the hippocampal tissue were measured by enzyme- linked immunosorbent assay. Blood samples were collected from the abdominal aorta to measure hemorheological indices. The morphological changes of hippocampal CA1 neurons were observed by HE staining. Results Compared with the model group, the high- dose Siwu Decoction had significantly reduced escape latency (P<0.05), a significantly increased target quadrant ratio (P<0.05), significantly reduced hippocampal AChE and ET- 1 levels (P<0.05), significantly increased hippocampal 5- HT and VEGF levels, and significantly reduced whole blood viscosity, plasma viscosity, and erythrocyte aggregation index (P<0.05). There were significant differences only in plasma viscosity and erythrocyte aggregation index between the high- and low- dose Siwu Decoction groups (P<0.05). Compared with the model group, the Siwu Decoction groups had reduced loss of hippocampal CA1 pyramidal cells, ordered arrangement of nerve fibers, and karyopyknosis in few cells. Conclusion Siwu Decoction shows certain efficacy in the treatment of VD, and its action mechanism involves regulating hippocampal AChE, 5- HT, ET- 1, and VEGF and improving hemorheology.