Aim To explore the effect of Buyang Huanwu decoction on anti-atherosclerosis by regulating the phenotypic transformation of vascular smooth muscle cells and serum inflammatory response based on Wnt/β-catenin signaling pathway. Methods 50 ApoE－/－ mice were randomly divided into model group, Buyang Huanwu decoction modified (low, medium and high dose) groups, and atorvastatin group, with 10 mice in each group; 10 C57BL/6J mice with the same genetic background were set as the control group. The mice of control group were fed with regular forages, while the mice of other five groups were fed with high-fat forages for 8 weeks for model replication. From the 9th week, they were continuously gavaged for 4 weeks. After 12 weeks, the mouse aortic roots were isolated and paraffin sections were prepared. Oil red O staining was used to observe the lipid content of aortic sinus. Immunohistochemical method was used to detect the expression level of bone bridge protein (OPN). Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) in serum. Western blot was used to detect the protein expressions of Wnt1, β-catenin and c-myc in mice aorta. RT-PCR was used to detect the expressions of Wnt1 and β-catenin gene. Results Buyang Huanwu decoction modified (low, medium and high dose) could reduce the lipid content and OPN expression in the aortic sinus of As model mice, reduce serum levels of IL-6 and TNF-α, IL-1β and MCP-1 in mice, and downregulate the expression of Wnt1 and β-catenin protein and gene. Conclusion Buyang Huanwu decoction modified exerts an anti-atherosclerosis effect by regulating inflammatory response, and some of the mechanisms may be related to inhibiting the activation of the Wnt/β-catenin signaling pathway.