Several predisposing factors have been incorporated into the worldwide increased prevalence of insulin resistance (IR), among them high caloric intake, sedentary lifestyle, aging, as well as genetic factors. Vildagliptin (VIL) is an oral hypoglycemic agent belonging to the dipeptidyl peptidase-4 inhibitor family. It has been reported to show multi-functional biological activities beyond its anti-hyperglycemic effect. The objective of the current study is to investigate the modulatory effect of VIL on hepatic complications, oxidative stress and lipoprotein abnormalities associated with IR in rats. In the current study, we have induced IR in rats through the combined administration of (10%) fructose in the drinking water with high-fat diet (HFFD) for 8 consecutive weeks. Animals were randomly allocated into three groups, the normal group, the HFFD, as well as the HFFD treated orally with VIL (10 mg/kg) for 8 consecutive weeks. Bodyweight indices, metabolic alterations, lipoprotein abnormalities, and oxidative stress biomarkers were markedly attenuated after VIL treatment. Furthermore, VIL significantly decreased the inflammatory response via inhibiting the nuclear factor-kappa B pathway. Moreover, VIL succeeded to ameliorate the hepatic DNA parameters. This study depicts that the oral daily treatment of the HFFD with VIL exerted a new modulatory activity on the hepatic complications and the lipoprotein abnormalities associated with IR through its complementary antioxidant, anti-inflammatory, and anti-hyperlipidemic effects.