Our study found that inhibition of Hedgehog pathway intensifies colon inflammation in mice. Inflammatory bowel disease (IBD) is a debilitating disorder with limited treatment options. Genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. We thus, in this study, identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.