Objective To explore a combination of resveratrol, berberine, curcumin and artesunate with a reasonable dose ratio to obtain the most effective and safest compound combination to provide an alternative selection for the patients with atherosclerosis and statin intolerance. Methods The atherosclerotic model in apolipoprotein E-knockout (ApoE^-/-) mice was established by high fat diet. Four compound of Chinese medicine including resveratrol, berberine, curcumin and artesunate were divided into 9 groups according to orthogonal test table L₉(3⁴). Through evaluating the degree of atherosclerosis and the level of low-density lipoprotein cholesterol（LDL-C） in each group, the most effective and safest combination of 4 compounds were obtained and verified. Results According to the therapeutic effect on blood LDL-C and aortic atherosclerotic plaque, the range analysis of orthogonal experiment suggested the best compound combination, which was: resveratrol 1.25 mg/(kg·d), berberine 0.625 mg/(kg·d), curcumin 12.5 mg/(kg·d), artesunate 6.25 mg/(kg·d). In verification phase, it was shown that the traditional Chinese medicine combination group had smaller atherosclerotic plaque areas, lower liver injury than the single drug group (all P<0.05). Conclusions Through orthogonal test, we obtained a best compound combination of traditional Chinese medicine in all combination groups, which could prevent atherosclerosis and was verified to be effective and safe. This study provided a reference method in clinical transformation for traditional Chinese medicine.