Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11-deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human ortholog of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium-infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore, an epithelial cell-intrinsic noncanonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface. Display omitted •Enteric pathogens activate an epithelial cell-intrinsic noncanonical inflammasome•Caspase-4 mediates infected epithelial cell extrusion via induction of pyroptosis•Caspase-4 mediates IL-18 cleavage in human epithelial cells•Caspase-11 activation controls bacterial burdens in the intestine of mice Intestinal epithelial cells are the first line of defense against pathogens. Knodler et al. report that a noncanonical inflammasome in these cells recognizes intracellular and extracellular bacterial pathogens. Inflammasome activation limits Salmonella colonization via infected epithelial cell extrusion and proinflammatory cytokine release, representing a potent mucosal antimicrobial defense mechanism.