Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce pathology are elusive. Here, we show that gastrointestinal MNV infection leads to widespread IL-1β maturation in MNV-susceptible STAT1-deficient mice. MNV activates the canonical Nlrp3 inflammasome in macrophages, leading to maturation of IL-1β and to Gasdermin D-dependent pyroptosis. STAT1-deficient macrophages displayed increased Nlrp3 inflammasome responses, and inactivation of either Nlrp3 or Gasdermin D delayed lethality of Stat1-/- mice after gastrointestinal MNV infection. These results reveal a detrimental role for Nlrp3 inflammasome activation and ensuing Gasdermin D-driven pyroptosis in MNV-induced pathology, suggesting this innate immune signaling axis as a potential therapeutic target in norovirus-induced gastroenteritis.