Significance The intestinal immune system is able to control pathogens while tolerating and interpreting microbial cues from an abundant microbiome. The mechanisms of innate recognition are crucial to differentiating between pathogen and commensal in this tissue and to mounting an appropriate inflammatory response. Persistent inflammation can alter the cellular architecture and physiology of the gut and have lasting impact on the nutritional state of children who face frequent infection with certain enteric pathogens. We demonstrate that the widespread parasite Cryptosporidium acts as a potent trigger for an enterocyte-intrinsic inflammasome that depends on the NOD-like receptor pyrin domain-6 and results in the local release of the proinflammatory cytokine IL-18.