Hypercholesterolemia is a well-established risk factor for kidney injury that can lead to chronic kidney disease (CKD). Many clinic data show that dipeptidyl peptidase-4 (DPP-4) inhibitor is protective against kidney damage in diabetes patients. The goal of this study was to investigate the possible protective effects of teneligliptin against kidney injury in apolipoprotein E knockout (ApoE^−/−) mice. Eight-week-old male ApoE^−/− mice were randomly divided into the following 3 groups: a control group fed a normal diet (ND group), a group fed a high cholesterol diet (HD group) or a group fed HD mixed with teneligliptin (HD + Tene group). All groups received different treatments for 6 weeks. The metabolic characteristics of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and creatinine (Cre) were lower in ApoE^−/− HD + Tene mice than ApoE^−/− HD mice. Oil-red O staining revealed excessive lipid deposition in the kidneys of ApoE^−/− HD mice; however, it was significantly suppressed in the ApoE^−/− HD + Tene mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) gene and protein expression was lower in the kidney tissue of ApoE^−/− HD + Tene mice than ApoE^−/− HD mice. These results indicate that teneligliptin may provide a potential therapeutic target for kidney damage from hypercholesterolemia.