The study investigates the role of gasdermin D (GSDMD), an inflammasome-activated pore-forming protein, in influenza virus-induced mortality. GSDMD ablation in knockout (KO) mice significantly reduces weight loss, lung dysfunction, histopathology, and mortality compared to wild-type (WT) mice, despite similar viral loads. Infected Gsdmd−/− mice exhibit decreased inflammatory gene signatures, particularly in neutrophil activation, as shown by lung transcriptomics. This is supported by reduced detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. In vitro, directly infected neutrophils release DNA and tissue-damaging enzymes, which are largely dependent on GSDMD. Depletion of neutrophils in infected WT mice recapitulates the reductions in mortality, lung inflammation, and dysfunction observed in Gsdmd−/− animals, but does not have additive protective effects in Gsdmd−/− mice. These findings suggest that GSDMD promotes lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic approach to treat severe influenza.The study investigates the role of gasdermin D (GSDMD), an inflammasome-activated pore-forming protein, in influenza virus-induced mortality. GSDMD ablation in knockout (KO) mice significantly reduces weight loss, lung dysfunction, histopathology, and mortality compared to wild-type (WT) mice, despite similar viral loads. Infected Gsdmd−/− mice exhibit decreased inflammatory gene signatures, particularly in neutrophil activation, as shown by lung transcriptomics. This is supported by reduced detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. In vitro, directly infected neutrophils release DNA and tissue-damaging enzymes, which are largely dependent on GSDMD. Depletion of neutrophils in infected WT mice recapitulates the reductions in mortality, lung inflammation, and dysfunction observed in Gsdmd−/− animals, but does not have additive protective effects in Gsdmd−/− mice. These findings suggest that GSDMD promotes lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic approach to treat severe influenza.