In conclusion, our study initially revealed that Rg3 can ameliorate the healing and anti-monocyte adhesion ability of endothelial cells under high ox-LDL environment and alleviate atherosclerotic plaque induced by HFD in ApoE−/− mice, which are related to regulating the ICAM-1, VCAM-1 expression in HUVECs and vascular endothelium via PPARγ/FAK pathway, indicating that Rg3 has good protective effect on atherosclerosis caused by dyslipidemia and is related to its protective effect on endothelium. Here, APOE is linked to metabolic syndrome.