Neutrophil extrusion of neutrophil extracellular traps (NETs) and concomitant cell death (NETosis) provides host defense against extracellular pathogens, while macrophage death by inflammasome-mediated death (pyroptosis) enables defense against intracellular pathogens. Here we report the surprising discovery that gasdermin D (GSDMD) connects these cell death modalities. We show that neutrophil exposure to cytosolic lipopolysaccharide or cytosolic Gram-negative bacteria activates non-canonical (caspase-4/11) inflammasome signaling and triggers GSDMD-dependent neutrophil death. Remarkably, GSDMD-dependent death induces neutrophils to extrude antimicrobial NETs. Caspase-11 and GSDMD are required for neutrophil plasma membrane rupture during the final stage of NET extrusion. Unexpectedly, caspase-11 and GSDMD are also required for early features of NETosis, including nuclear delobulation and DNA expansion; this is mediated by the coordinate actions of caspase-11 and GSDMD in mediating nuclear membrane permeabilization and histone degradation. In vivo application of DNase I to dissolve NETs during murine bacterial challenge increases bacterial burden in wild-type but not Casp11-/-and Gsdmd-/-mice. Our studies reveal that neutrophils employ an inflammasome- and GSDMD-dependent mechanism to activate NETosis as a defense response against cytosolic bacteria.