Objective: To investigate the combination therapeutic effect of sitagliptin and ezetimibe on atherosclerosis in apoE–/– mice and explore the related mechanisms. Methods: The 6-week apoE–/– mice were randomly divided into 5 groups: normal group, high-fat diet group, Sitagliptin group, Ezetimibe group, and combination therapy group. The levels of blood glucose and lipid were detected by biochemical detector. Atherosclerotic plaque area in aortas were measured by oil red O staining. The concentration of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and TNF-α in serum were determined by ELISA assay. The expressions of NF-κB p65 were analyzed by Western blot. Results: Compared to sitagliptin or ezetimibe, combination therapy group can further inhibited high-fat diet-induced the increase of total cholesterol (TC) and low density lipoprotein cholesterin (LDL-C) levels (P<0.05), while increased the level of high density lipoprotein cholesterol (HDL-C) (P<0.05). Moreover, the inhibition of atherosclerotic plaque formation, VCAM-1, MCP-1 and TNF-α concentration, and NF-κB p65 protein expression were more much pronounced in combination therapy group (P<0.05). Conclusion: Our data demonstrates that combination of sitagliptin and ezetimibe can further inhibit the atherosclerotic plaque formation and prevent atherosclerosis in apoE–/– mice, which may through activation of NF-κB signaling pathway.