Scope: -casofensin, also known as peptide -CN(94-123), is a milk bioactive peptide that modulates the intestinal barrier through its action on goblet cells. Here, we evaluated whether oral administration of -casofensin can prevent indomethacin-induced injury of the jejunum in rats. Methods and results: Rats received -casofensin (0.01–100 M) or tap water by daily gavage (4 L/g) for eight days, then two subcutaneous injections of indomethacin (10 mg/kg, days 9 and 10) and were euthanized on day 12. In vitro, we investigated the effects of -casofensin on the restitution of a wounded monolayer. Preventive administration of -casofensin (100 M) reduced intestinal macroscopic and microscopic damage induced by indomethacin. -casofensin also prevented the depletion of goblet cells and increased myeloperoxidase activity, as well as tumor necrosis factor-ɑ (TNF-ɑ) expression and immunostaining of active caspase-3 in the jejunum of rats treated with indomethacin. In wound healing experiments, -casofensin promoted epithelial restitution with no effect on cell proliferation. This effect was inhibited by pre-incubation with an anti-CC chemokine receptor 6 (CCR6) neutralizing antibody. Conclusions: -casofensin exerts protective effects in indomethacin-induced enteritis through preservation of goblet cells and improvement in wound healing. -casofensin could therefore become vital in nutritional programs for the prevention of intestinal diseases.