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Abstract Background Glucagon-like peptide-2 (GLP-2) enhances intestinal repair and attenuates inflammation in preclinical inflammatory bowel disease (IBD) models, making GLP-2 analogues attractive candidates for IBD therapy. Glepaglutide is a long-acting GLP-2 receptor agonist in clinical development for treatment of short bowel syndrome. Here, we investigated if glepaglutide is therapeutically beneficial in rats with small intestinal inflammation. Methods Small intestinal inflammation was induced with indomethacin in naive Wistar rats, followed by glepaglutide administration at different disease stages. Glepaglutide was administered in co-treatment and post-treatment regimens. Small intestinal length and concentrations of inflammatory markers α-1-acid glycoprotein and myeloperoxidase were used to assess anti-inflammatory effects. Small intestinal mass was evaluated to determine intestinotrophic effects. Results Glepaglutide co- and post-treatment significantly reduced severity of small intestinal inflammation, evidenced by reversed small intestinal shortening and decreased α-1-acid glycoprotein and/or myeloperoxidase concentration(s). Co- and post-treatment with glepaglutide also significantly increased small intestinal mass, indicating intestinal regenerative effects. Similar effects were observed in naive rats after glepaglutide treatment. Conclusion Glepaglutide has anti-inflammatory and intestinotrophic effects without the need for pre-treatment in a rat model of small intestinal inflammation. Thus, glepaglutide is of potential clinical interest for patients with IBD.