Objective To explore the effect of Xiaoxianxiong Decoction on vascular endothelial injury in mice with hyperlipidemia ( Hyperlipemia, HLP). Methods Thirty-six C57BL/ 6 mice were randomly divided into control, model, low dose group (0. 03 g / mL Xiaoxianxiong Decoction), medium dose (0. 06 g / mL Xiaoxianxiong Decoction), high dose group (0. 12 g / mL Xiaoxianxiong Decoction), and Lovastatin (2. 5 mg / kg lovastatin) groups. Six rats in each group were fed a high fat diet for 8 weeks to establish the HLP model and administered corresponding drugs for treatment. During the administration period, the general behavioral state of mice in each group was observed and mice were weighed once a week. HE staining was used to observe histopathological changes of aortic vessels. Immunohistochemistry was used to detect expression of von Willebrand factor ( vWF) in aortic tissues of mice. qRT-PCR was used to measure mRNA levels of vascular endothelial growth factor (VEGF), EPH receptor B4 (EphB4), and Ephrin-B2 (EphrinB2) in aortic tissues of mice. Western blot was used to measure the protein levels of VEGF, EphB4, and EphrinB2 in aortic tissues of mice. Results Compared with the control group, the activity and food intake of mice in the model group was decreased, hair was poor, weight had increased, and the expression levels of vWF, VEGF, EphB4, and EphrinB2 were increased in aortic tissue. Compared with the model group, the activity and food intake of mice in each dose group of Xiaoxianxiong Decoction and the Lovastatin group were increased, hair was brighter, weight was reduced, and the expression levels of vWF, VEGF, EphB4, and EphrinB2 were decreased in aortic tissue (P< 0. 05). Compared with the low dose group, mRNA and protein expression levels of VEGF, EphB4, and EphrinB2 were decreased in medium and high dose groups ( P< 0. 05). Conclusions Xiaoxuai decoction inhibits the development of HLP and protects the vascular endothelium of mice.