Sitagliptin (SIT) is an antidiabetic used worldwide to ameliorate the hyperglycemia and insulin insensitivity induced dysmetabolism. In this study, we investigated the effect of sitagliptin and vitamin E on metabolic dysfunction in high-fat diet (HFD) fed rats. Sixty-four male rats were allocated into 8 groups (n = 8) as follow; control, control + vitamin E, control + sitagliptin, control + sitagliptin + vitamin E, HFD, HFD + vitamin E, HFD + sitagliptin and HFD + sitagliptin + vitamin E. Control groups were fed with chow diet for 15 weeks, while HFD groups were fed with HFD for the same duration. Vitamin E and sitagliptin were administered in the last 4 weeks of the study. At the end of the 15th week, body weight, liver weight/body weight ratio, weight gain, glucose, lipid profile, liver enzymes, adiponectin and pro-inflammatory cytokines as interleukin 6 (IL-6), high sensitive C reactive protein (hs-CRP) and tumour necrosis factor-α (TNF-α) were measured. Additionally, gene expressions of senescence marker protein 30 (SMP30), Bcl-2, and Bax were measured. Total antioxidant capacity (TAC) and thiobaribituric acid reactive substances (TBARS) were assayed. HFD increased TBARS, IL-6, hs-CRP and TNF-α significantly and decreased TAC and adiponectin. Sitagliptin produced a comparable result through increasing adiponectin, sitagliptin alone or in combination with vitamin E increased the TAC, and gene expression of SMP30 and Bcl-2 and decreased TBARS with downregulation of the overexpressed Bax. Vitamin E, as a natural antioxidant, ameliorates the oxidative stress with insignificant change in lipid profile and inflammatory cytokine levels. Concomitant sitagliptin and vitamin E reduced the hepatic dysfunction induced by HFD.