Inflammatory caspases sensing lipopolysaccharide (LPS) to drive gasdermin (GSDM)-mediated pyroptosis is an important immune response mechanism for anti-infection defense in mammals. In this work, we resolved an LPS-induced and GSDM-gated pyroptosis signaling cascade in Cnidarians. Initially, we identified a functional GSDM protein, HyGSDME, in , executing cytosolic LPS-induced pyroptosis in a caspase-dependent manner. Further, we identified a proinflammatory caspase, HyCaspA capable of sensing cytosolic LPS by an uncharacterized N-terminal domain relying on its unique hydrophobic property, thereby triggering its oligomerization and self-activation. Subsequently, the LPS-activated HyCaspA cleaved an apoptotic caspase, HyCARD2, to trigger HyGSDME-gated pyroptosis. Last, HyGSDME exhibited an enriched distribution on the ectodermal layer of polyps, exerting a canonical immune defense function against surface-invading bacteria. Collectively, our work resolved an ancient pyroptosis signaling cascade in , suggesting that inflammatory caspases sensing cytosolic LPS to initiate GSDM-gated pyroptosis are a conserved immune defense mechanism from Cnidarians to mammals.