Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m−/− mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m−/− animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m−/− mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m−/− mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention. •Human patients display increased IRAK-M expression during IBD and colorectal cancer.•Irak-m−/− mice are protected from colitis and colitis associated tumorigenesis.•Irak-m splice variant robustly activates NF-κB signaling. Abnormal inflammatory responses in the gut can lead to the progression of severe diseases such as inflammatory bowel disease and colitis associated cancer. In order to improve the treatment options for patients afflicted with these diseases, we investigated a protein termed interleukin receptor associated kinase M (IRAK-M) that is implicated in the regulation of inflammation. In this study, we used mice as a model system to gain insight into the contribution of IRAK-M to colitis and colitis-associated cancer pathogenesis. Our findings suggest mice containing a mutant IRAK-M are protected against both ulcerative colitis and colitis associated cancer.