Aim To observe the effects and mechanism of glycyrrhiza acid （GA） on lipid metabolism and development of atherosclerotic lesions in apolipoprotein E gene knockout （ApoE^－/－） mice. Methods Eighteen female ApoE^－/－ mice were randomly divided into control group and glycyrrhiza acid treatment group. All mice were fed with Western diet for 12 weeks, glycyrrhiza acid 100 mg/（kg·d） was intragastrically given to hyperlipidemic mice and 0.9% NaCl as the control. The weight of mice was detected per 4 weeks, the levels of plasma lipids and glucose were determined enzymatically, serum paraoxonase 1 （PON1） activity was measured by using paraoxon as the substrate. The extent of aortic atherosclerosis was examined both in oil red O-stained cross-sections of the proximal aorta （8 m cryosections） and by en face analysis with quantitation using Image J System. The expression levels of gene in liver were detected by real-time PCR and Western blot. Results The average weight of mice was increased and dyslipidemia was aggravated during being fed with Western diet. The increasing level of mice weight, the level of plasma triglycerides and glucose had no obvious change between both groups. However, the level of total cholesterol was statistically decreased （P<0.05） in ApoE^－/－ mice with glycyrrhiza acid treatment compared with control group. In mice of glycyrrhiza acid group, the atherosclerotic lesions of aortic root and aorta were reduced by 21% to 22% versus control mice. Glycyrrhiza acid obviously up-regulated the mRNA level of scavenger receptor BⅠ （SR-BⅠ） and ATP-binding cassette transporter A1 （ABCA1） in mouse liver. Meanwhile, glycyrrhiza acid significantly increased the serum antioxidative enzymes PON1 activity by up-regulation of the PON1 expression level （P<0.01）, and the expression level of cellular methionine sulfoxide reductase A （MsrA） was also increased. Conclusions Glycyrrhiza acid inhibits the development of the atherosclerosis, the mechanism might be related to the regulation of cholesterol metabolism and improvement of antioxidation.