The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD. We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF-beta activated Kinase 1 (TAK1), a central regulator of cellular inflammatory actions. Activation of TAK1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD) as well as in DSS-induced and spontaneous IBD in mice. The role of TAK1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)-7-Oxozeaenol, a highly selective pharmacological inhibitor of TAK1. We found hyper-activation of TAK1 in patients with UC or CD and in murine models of IBD. Pharmacological inhibition of TAK1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD. We demonstrated that at the early phase of the disease activation of TAK1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK1 as crucial in promoting intestinal inflammation. Thus, the TAK1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.