This study evaluates whether melatonin can improve the structure of the small intestine and enhance adaptation in an experimental model of short bowel syndrome. Thirty Sprague-Dawley rats were divided randomly into three experimental groups of 10 animals each. In one group, only laparotomy was performed and these rats served as the sham-control group (G1). The remaining 20 rats underwent 90% small bowel resection (SBR) and formed the two experimental groups: the SBR/untreated group (G2), and the SBR/melatonin-treated group (G3). Rats in the SBR/untreated group received no therapeutic treatment. Rats in the SBR/melatonin-treated group received melatonin intraperitoneally for 3 weeks. The animals were weighed daily. All rats underwent relaparotomy on day 21 of the experiment. Remnant small bowel was excised and evaluated for villus height, total mucosal thickness, and crypt cell mitosis. After the 90% SBR, all animals suffered from diarrhea and weight loss between the first and the sixth postoperative days. The body weight of the SBR/melatonin group showed significant increases at the beginning of postoperative day 10 and day 21 in comparison to that of the SBR/untreated group. The rats treated with melatonin had significantly greater villus height and crypt cell mitosis compared to the sham-control group and the SBR/untreated group. In addition, the mucosal thickness was significantly increased in the SBR/melatonin-treated group compared to the SBR/untreated rats. These observations suggest that melatonin treatment increases villus height, total mucosal thickness, and crypt cell mitosis after massive SBR and it may exert a considerable effect on the mucosal adaptive response in short bowel syndrome in rats.