In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-κB, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and we found Nlrp12−/− mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12−/− mice showed elevated noncanonical NF-κB activation and increased expression of target genes that were associated with cancer, including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation, but the latter dominantly contributed to tumorigenesis. The noncanonical NF-κB pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3, and Nlrp12−/− cells have constitutively elevated NIK, p100 processing to p52 and reduced TRAF3. Thus, NLRP12 is a checkpoint of noncanonical NF-κB, inflammation, and tumorigenesis. ► Nlrp12−/− mice are significantly more susceptible to colitis-associated colon cancer ► NLRP12 is a negative regulator NIK, CXCL12, CXCL13, ERK, and AKT in vivo ► Hematopoietic and nonhematopoietic compartments contribute to Nlrp12−/− phenotype ► NLRP12 functionally interacts with and alters the balance of NIK and TRAF3