Ulcerative colitis and Crohn's disease are major inflammatory syndromes that affect millions of patients. Caspase-11 confers protection against Gram-negative enteropathogens, but its role during colitis is unknown. Here, we show that caspase-11 was constitutively expressed in the colon, and that caspase-11-deficient (caspase-11(-/-)) mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis. Notably, pro-inflammatory Prevotella species were strongly reduced in the gut microbiota of caspase-11(-/-) mice. Co-housing with wild-type mice leveled Prevotella contents, but failed to protect caspase-11(-/-) mice from increased susceptibility to DSS-induced colitis. We therefore addressed the role of caspase-11 in immune signaling. DSS-induced tissue damage, release of the pyroptosis/necroptosis marker HMGB1, and inflammatory cell infiltration in the gut were markedly increased in caspase-11(-/-) mice. Moreover, caspase-11(-/-) mice showed normal or increased production of mature interleukin (IL)-1 beta and IL-18, whereas IL-1 beta and IL-18 secretion was blunted in animals lacking both caspases 1 and 11. In conclusion, we showed that caspase-11 shapes the gut microbiota composition, and that caspase-11(-/-) mice are highly susceptible to DSS-induced colitis. Moreover, DSS-induced inflammasome activation relied on caspase-1, but not caspase-11. These results suggest a role for other caspase-11 effector mechanisms such as pyroptosis in protection against intestinal inflammation.