Aim The aim of this study was to investigate the possible protective effects of leflunomide, which has antioxidant and anti-inflammatory properties, against intestinal IR injury in rats. Materials and Methods Forty female Wistar albino rats were divided into six groups: control (n = 5), drug control (n = 7), sham operated (n = 7), IR alone (n = 7), IR plus vehicle ( IR + vehicle, n = 7) and IR plus 20 mg/kg leflunomide (IR + Leflunomide, n = 7). While rats were pretreated intragastrically with leflunomide (20 mg/kg) and vehicle in three doses prior to the experiment, respectively, in the IR + Leflunomide and IR + vehicle groups, no additional application was done in the IR alone group. Intestines were exteriorized, and the superior mesenteric artery was occluded for 45 min ischemia, and then the clamp was removed for 120 min reperfusion. After the experiment, the intestines were removed for biochemical and histological examinations. Additionally, blood samples were taken for measurements of antioxidant parameters. Results The intestinal IR significantly increased the MDA level and MPO activity; however, treatment with leflunomide reversed those findings (P < 0.05). The CAT activity of the IR + Leflunomide group was significantly higher than in the IR groups (P < 0.05). The SOD activity was increased in the intestinal IR group, and leflunomide treatment reversed that, too (P < 0.05). The light microscopic findings showed that IR caused mucosal necrosis and leflunomide treatment reduced the morphological alterations associated with IR (P < 0.05). Conclusion Intestinal IR injury may be reversed by the anti-inflammatory and antioxidant actions of leflunomide.