Abstract In vertebrates, pyroptosis is an intensely inflammatory form of programmed cell death which is dependent on Caspase 1 activation and release of cytoplasmic cytokines including IL-1β. This death pathway is critical for controlling pathogenic infection by mobilizing immune cells and stimulating the development of adaptive immune response. In invertebrates, however, due to the lack of adaptive immune response, it is still elusive whether Caspase 1-dependent cell death pathway exists. In this study, our data showed that Caspase 1-mediated cell death was activated by white spot syndrome virus (WSSV) infection to control the virus in shrimp. Caspase 1 had a higher expression level in hemocytes and lymphoid-like organ in shrimp and WSSV infection was significantly promoted upon the inhibition of Caspase 1 enzymatic activity. IL-1β-like protein was identified as the substrate of Caspase 1 and its interaction with Caspase 1 was validated ectopically and endogenously. Moreover, IL-1β like protein was released into extracellular contents under WSSV infection and Prophenoloxidase system was activated, resulting in the reduction of WSSV copies in vivo . Our data unraveled a previously unidentified mechanism through which Caspase 1-dependent cell death controlled virus infection in shrimp. Therefore, our study opened the possibility that an invertebrate cytokine network might be operative and regulate host defenses against virus infection as in vertebrates. Author Summary The elimination of infected cells by programmed cell death is considered as one of the most important anti-pathogen responses. Pyroptosis is one form of programmed cell death, which is mediated by Caspase 1 activation. Activated Caspase 1 can process the inactive precursors of interleukin 1β (IL-1β) into mature inflammatory cytokines to induce potent immune responses. Meanwhile, pyroptosis also induces morphologic changes, DNA fragmentation and chromatin condensation to destroy infected cells. However, due to the lack of efficient adaptive immune responses, it is still unclear whether Caspase 1-mediated cell death also exits and plays such an important role in defending hosts from pathogen invasion in invertebrates. In our data, Caspase 1 gene was characterized and Caspase 1-mediated cell death pathway was validated in shrimp. The Caspase 1-mediated cell death pathway was enhanced by white spot syndrome virus (WSSV) infection to control the virus in shrimp. IL-1β-like protein was cleaved by Caspase 1 and released into extracellular contents under WSSV infection to activate Prophenoloxidase system, leading to the reduction of WSSV copies in shrimp in vivo. On the other hand, silencing of Caspase 1 or IL-1β-like gene facilitated virus infection in shrimp. Our study indicated that Casapase-1-mediated cell death played an important antiviral role in shrimp against WSSV infection and opened the possibility that an invertebrate cytokine network might be operative.