The mammalian family of mitogen-activated protein kinases (MAPKs) is activated by diverse extracellular and intracellular stimuli, and thereby they play an essential role in connecting cell-surface receptors to changes in transcriptional programs. The MAPK signaling pathways regulate a wide range of cellular activities and have been implicated in the pathogenesis of several diseases, including inflammatory bowel disease (IBD). This review summarizes recent findings on the regulatory mechanism of MAPK signaling pathways, focusing on nuclear targets and their role in IBD. Finally, it summarizes how these signaling pathways have been exploited for the development of therapeutics and discuss the current knowledge of potential MAPK inhibitors and their anti-inflammatory effects in clinical trials related to IBD.