Abstract Introduction Intestinal ischemia-reperfusion is still a relevant clinical problem, especially in newborns and in the elderly. In this piece of work, we check the utility of curcumin and dexmedetomidine to overcome the damage induced by reperfusion, both locally and in distant organs, using α-tocopherol as a comparison. Methods In female Wag/RijHsd rats, the superior mesenteric artery was clamped for 1 h; then, animals were allowed 4 h of reperfusion. Curcumin (200 mg/kg, oral) was given 24 h and 2 h before clamping; α-tocopherol (20 mg/kg, i.p.) was administered 2 h before ischemia, and dexmedetomidine (10 or 40 mg/kg, s.c.; dex-10 and dex-40, respectively) was given 15 minutes before ischemia. Blood samples and terminal ileum were collected. Additionally, a D-xylose absorption test was performed to evaluate intestinal absorption; 1h after D-xylose administration, D-xylose plasma levels were quantified (mg/ml). Results All of the treatments reduced histological damage assessed with Chiu's scale (non-treated, 2.6 ± 0.75; curcumin, 1.54 ± 0.8; dex-10, 1.47 ± 0.7; dex-40 1.43 ± 0.9; α-tocopherol, 1.01 ± 0.8) and improved absorption of D-xylose (healthy rats 2.06 ± 0.07; non-treated, 1.18 ± 0.07; curcumin 1.76 ± 0.30; dex-10, 2.29 ± 0.20; dex-40, 2.25 ± 0.26; α-tocopherol 1.66 ± 0.21). Dexmedetomidine improved renal function (it reduced both creatinine and urea in serum). The elevation of liver enzymes in serum was not improved by any of the drugs. Conclusions The three drugs proved to be useful, though α-tocopherol was more efficient regarding histological damage, and only dexmedetomidine restored D-xylose absorption to normal values.