The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp−/−;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis. Display omitted •IL-18/IL-18R signaling in intestinal epithelial cells promotes DSS-induced colitis•Hyperactive epithelial IL-18 signaling drives goblet cell depletion during colitis•Epithelial IL-18 signaling prevents goblet cell maturation prior to colitis•IL-18 intercepts the transcriptional program controlling goblet cell development Production of the cytokine IL-18 by epithelial cells, previously thought to protect the mucosal barrier from the effect of inflammation, is critical to drive the pathologic breakdown of intestinal barrier integrity, directly inhibiting goblet cell maturation prior to the onset of colitis.