Longhu Rendan (LHRD), a Chinese traditional compound medicine, has a remarkable treatment effect on motion sickness for about half a century. However, the role of LHRD in atherosclerosis treatment is still unclear. In this study, LHRD treatment significantly diminished total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in apolipoprotein E gene-knockout (ApoE-/-) mice fed with high fat and high cholesterol diet (western diet). Besides, LHRD treatment significantly reduced atherosclerotic lesion and plaques formation in both aortic roots and aortic trees. Furthermore, immunofluorescence staining in aortic roots demonstrated that LHRD treatment inhibited lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) expression in atherosclerotic plaques. These results indicated that LHRD ameliorated atherosclerosis via reducing serum levels of TC, TG, and LDL-C as well as LOX-1 expression, subsequently attenuating atherosclerotic lesion and lipid deposition. In conclusion, LHRD could significantly attenuate experimental atherosclerosis and might be a novel potential drug for the prevention and treatment of atherosclerosis.