Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis; however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an mouse model lacking in intestinal epithelia. deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal-regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to deletion, suggesting the protective role of Regnase-1 against colon tumor growth was dependent on IL-17 signaling triggered by gut microbes. Analysis of the knockout mouse model demonstrated that the tumor-suppressive effect of depended on expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low expression in colorectal cancer tissue was related to poor prognosis. Therefore, represses colon tumor growth by regulating IL-17 signaling via mRNA degradation. could be a potential therapeutic target in colon tumors.