Despite the growing number of cancer cases, current anti-cancer treatments greatly improve patients’ survival. Although it is efficient, radiotherapy can induce severe complications. The abdomino-pelvic area regroups cancers with high prevalence (prostate, bladder…) and organs at risk during radiotherapy. Colon and rectum display severe side effects in 20% of patients 20 years after treatment. Colorectal fibrosis is the most frequent of these complications. Existing treatments are only palliative. Mesenchymal Stem Cells (MSCs) promote tissue regeneration in a wide variety of pathologies, fibrosis included, and thus seem fitted for the treatment of radiation-induced disorders. However, the effects of MSCs on tumor growth and radiotherapy induced damages are still unclear. Our work evaluates the safety and efficacy of MSC transplantation before and after colorectal radiotherapy in rats. In a model of chemically-induced colorectal carcinogenesis, followed by radiotherapy, MSC injection suppressed tumor growth by modifying the phenotype of T lymphocytes and macrophages of the tumor microenvironment. In a second model, transplanted MSCs suppressed radiation-induced fibrosis. Two proteins secreted by MSCs, HGF and TSG-6, are responsible for inhibiting extracellular matrix-producing cells, which are the major contributors to fibrosis. MSC injection was associated with increased survival in both studies. Overall, our results support the use of MSCs to treat the side effects of abdomino-pelvic radiotherapy.