Aim To investigate the effect and possible mechanism of total flavones of dracocephalum moldavica (TFDM) on atherosclerosis lesions in apolipoprotein E gene deficient (ApoE－/－) mice. Methods ApoE－/－ mice were randomly divided into model group, simvastatin group and TFDM high, medium, low dose group, C57BL/6J mice were set as the normal control group. After treated for 12 weeks, the mice were sacrificed and plasma lipids were determined, the area of atherosclerotic plaques and the ratio of plaque area to aorta were measured by HE staining, the expressions of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), proliferating cell nuclear antigen (PCNA) in aortic atherosclerotic lesions were detected by immunohistochemistry analysis. Results Compared with the model group, the levels of triglyceride (TG) and low density lipoprotein cholesterol (LDLC) was decreased significantly in treatment group. The atherosclerotic lesions reduced and the ratio of plaque area to aorta decreased in TFDM groups. The expression of ICAM-1, VCAM-1 and PCNA were down-regulated by TFDM. Conclusion TFDM can inhibit atherosclerosis formation which involved in decreasing the level of plasma lipids and weakening the expression of ICAM-1, VCAM-1 and PCNA in the aorta wall.