Patients who undergo pelvic or abdominal radiotherapy may develop acute and/or chronic side effects resulting from gastrointestinal tract (GIT) alterations. In this study, we address the question of the regenerative capability of mesenchymal stem cells (MSC) after radiation-induced GIT injury. We also propose cellular targets of MSC therapy. We report that the infusion of human bone marrow-derived MSC (hMSC) provides a therapeutic benefit to NOD/SCID mice undergoing radiation-induced GIT failure. We observed that hMSC treatment brings about fast recovery of the small intestine (structure and function) in mice with reversible alterations and extends the life of mice with irreversible GIT disorders. The effects of hMSC are a consequence of their ability to improve the renewal capability of small intestinal epithelium. hMSC treatment favors the re-establishment of cellular homeostasis by both increasing endogenous proliferation processes (Ki67 immunostaining) and inhibiting apoptosis (TUNEL staining) of radiation-induced small intestinal epithelial cells. Our results suggest that MSC infusion may be used as a therapeutic treatment to limit radiation-induced GIT damage.