Gasdermin E (GSDME) is identified as a master switch for neutrophil lytic pyroptotic death, controlling the mode of neutrophil death and dictating host inflammatory outcomes. GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival but specifically precludes pyroptosis and shifts neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, GSDME disruption can switch caspase-3-mediated pyroptosis to apoptosis, providing a potential therapeutic target for infectious and inflammatory diseases.Gasdermin E (GSDME) is identified as a master switch for neutrophil lytic pyroptotic death, controlling the mode of neutrophil death and dictating host inflammatory outcomes. GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival but specifically precludes pyroptosis and shifts neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, GSDME disruption can switch caspase-3-mediated pyroptosis to apoptosis, providing a potential therapeutic target for infectious and inflammatory diseases.