RNA-binding protein 47 (RBM47) is required for embryonic endoderm development, but a role in adult intestine is unknown. We studied intestine-specificRbm47-knockout mice (Rbm47-IKO) following intestinal injury and made crosses intoApcMin/+mice to examine alterations in intestinal proliferation, response to injury, and tumorigenesis. We also interrogated human colorectal polyps and colon carcinoma tissue.Rbm47-IKOmice exhibited increased proliferation and abnormal villus morphology and cellularity, with corresponding changes inRbm47-IKOorganoids.Rbm47-IKOmice adapted to radiation injury and were protected against chemical-induced colitis, withRbm47-IKOintestine showing upregulation of antioxidant and Wnt signaling pathways as well as stem cell and developmental genes. Furthermore,Rbm47-IKOmice were protected against colitis-associated cancer. By contrast, agedRbm47-IKOmice developed spontaneous polyposis, andRbm47-IKOApcMin/+mice manifested an increased intestinal polyp burden.RBM47mRNA was decreased in human colorectal cancer versus paired normal tissue, along with alternative splicing of tight junction protein 1 mRNA. Public databases revealed stage-specific reduction in RBM47 expression in colorectal cancer associated independently with decreased overall survival. These findings implicate RBM47 as a cell-intrinsic modifier of intestinal growth, inflammatory, and tumorigenic pathways.