Norovirus (NoV) infection contributes to more than 230,000 deaths from 23 million infections per year across the globe and can cause a major global pandemic every 2- 3 years. There is limited knowledge about the immune sensors involved in NoV infection in spite of discoveries that all three interferon (IFN) signaling pathways (Type I, II and III) are involved in host recognition and antiviral signaling against NoV infection. MDA5 and to a limited extent Toll-like receptor (TLR) 3 are the only immune sensors known to play role in detection NoV RNA. In the current study the role of the inflammasome, another arm of our innate immunity, in detection of MNV and induction of proinflammatory cytokines was investigated. Results indicated that MNV infection of LPS-primed macrophages lead to induction of cell death followed by activation of the inflammasome response, as evidenced by the release of IL-1β in WT cells. We identified that inflammasome activation is mediated by the NLRP3 arm as no IL-1β was released from Caspase-1, ASC or NLRP3 deficient cells. We suggest that inflammasome activation is an antiviral response as MNV replication was significantly enhanced upon infection of the inflammasome deficient cells. Collectively our data support the notion that MNV infection results in inflammasome activation and this process is triggered by induction of cell death. These results contribute to the elucidation of the underlying principles of immune detection and response to NoV infection, areas that are currently deficient in our understanding of NoV disease.