Ulcerative colitis and Crohn's disease are the two entities of chronic inflammatory bowel diseases (IBD). One of the main pathogenic mechanisms is probably a dysregulated immune response triggered by products of the enteric bacterial flora. The goal of this study was to evaluate the effects of the p38 mitogen‐activated protein kinase (MAPK) inhibitor SB203580 on inflammatory responses using the DSS‐induced experimental colitis model in mice reflecting human IBD. We found that SB203580 improved the clinical score, ameliorates the histological alterations, and reduces the mRNA levels of proinflammatory cytokines. In addition to p38 kinase activity, the “classical” and the “alternative” NF‐κB pathways were also strongly activated during colitis induction. All three pathways were drastically down‐regulated by SB203580 treatment. An analysis of the molecular basis of NF‐κB activation revealed that Rip‐like interacting caspase‐like apoptosis‐regulatory protein kinase (RICK), a key component of a pathway leading to NF‐κB induction, is also strongly inhibited by SB203580. Since RICK is an effector kinase of NOD2, an intracellular receptor of bacterial peptidoglycan, these results support the notion that NOD signaling could play a pivotal role in the IBD pathogenesis. Thus, RICK could represent a novel target for future therapies in human IBD.