Objectives: This study aimed to assess the possible antioxidant role of sitagliptin on intestinal ischemia/reperfusion (II/R)-mediated tissue injury. Methods: Forty-five male Sprague-Dawley rats were randomly assigned into three groups: Sham group (operation without clamping), II/R group (operation with clamping) and Sitagliptin pretreated group (300 mg/kg/day; orally by gavage) for 2 weeks before II/R insult. II/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for biochemical assessment of oxidative stress parameters. Results: Pretreatment with sitagliptin remarkably alleviated the oxidative stress response induced by I/R in the jejunum manifested by a marked reduction of the pro-oxidant NOX-2 enzyme level, the lipid peroxidation marker, MDA content and the nitrosative stress indicator, NO content as well as replenishing the key cellular enzymatic antioxidant, SOD activity. Conclusion: Sitagliptin has a potential antioxidant effect against II/R injury in rats and thus we assume sitagliptin may be a beneficial prophylactic drug in patients at risk of intestinal I/R injury.