Objective To explore the mechanism of Shenfu injection improving cognitive dysfunction in vascular dementia model mice. Methods Male Kunming mice were randomly divided into a Sham operation group, VD model group, SFI group(10 mL/ kg), L-Arg group(25 mg/ kg), and L-NAME group(10 mg/ kg)with nine in each group. The VD mouse model was established by repeated clipping and reperfusion of bilateral common carotid arteries and intraperitoneal injection of sodium nitroprusside. After modeling, each group was administered drugs for 21 days, and Sham operation and VD model groups were administered the same amount of physiological saline. The Morris water maze test assessed learning and memory abilities of mice, HE and Nissl staining was used to observe pathological changes. The Griess method was used to assess the NO concentration. ROS, MDA, and GSH contents were assessed by kits. iNOS, nNOS, and eNOS protein expression was assessed by Western blot analysis. Results Compared with the Sham operation group, the latency time of the VD group was prolonged in the Morris maze test, pathological damage in the hippocampal Ca1 region was obvious, NO, ROS, and MDA contents were increased, GSH activity was decreased(P<0. 01, P<0. 05), nNOS and iNOS expression was significantly increased, and eNOS protein expression was decreased(P<0. 01, P<0. 05). Compared with the VD group, L-Arg treatment group showed no significant improvements in learning or memory abilities, pathological damage in the hippocampal CA1 region, or expression of NO, ROS, MDA, and GSH. Compared with the VD group, learning and memory abilities in SFI and L-NAME groups were improved, pathological damage of the hippocampal Ca1 region was significantly improved, NO, ROS, and MDA contents were decreased, GSH activity was increased, eNOS protein expression was increased, and iNOS and nNOS protein expression was significantly decreased(P<0. 01, P<0. 05). Conclusions SFI improves cognitive dysfunction in VD mice, which may be related to the NOS/ NO pathway.