ETHNOPHARMACOLOGICAL RELEVANCE: Severe pneumonia (SP) represents an acute, critical condition characterized by high morbidity and mortality rates, along with numerous complications. The Qingfei Jiedu Huatan Formula (QJHF), a traditional Chinese medicine (TCM) formulation, is indicated for the treatment of severe pneumonia. However, its underlying therapeutic mechanisms remain uncertain. AIM OF THE STUDY: This study aimed to investigate the beneficial effects and molecular mechanisms of QJHF in the treatment of severe pneumonia. MATERIALS AND METHODS: The anti-inflammatory properties of QJHF were assessed using a Klebsiella pneumoniae-induced rat model of SP and LPS-induced MH-S cells. Network pharmacology and transcriptomics were employed to identify potential targets and elucidate the molecular mechanisms underlying QJHF's action against SP. Pyroptosis in lung tissue and MH-S cells was examined via immunofluorescence and scanning electron microscopy. The expression of the NLRP3 inflammasome and its upstream regulatory pathways was measured through Western blot analysis. RESULTS: QJHF was found to alleviate pulmonary edema, enhance lung pathology, and improve the blood oxygenation index, while reducing inflammatory cell infiltration, expression of inflammatory factors, and lactic acidosis in SP rats. Serum containing QJHF-containing serum significantly reduced the secretion and transcription of inflammatory factors in MH-S cells. Network pharmacology and RNA-Seq analysis revealed potential targets modulated by QJHF against SP, showing a significant association between these targets and NLRP3 within the PPI network. Pathway enrichment analysis suggested that the NOD-like receptor, TNF, NF-κB, and JAK/STAT signaling pathways might regulate the NLRP3 inflammasome and coordinate the inflammatory response. Additionally, QJHF was shown to suppress NLRP3 inflammasome activation in rats with SP and in MH-S cells, which corresponded with markedly reduced levels of TNFR1, TRAF2, TAK1, phosphorylated p65, IκBα, JAK2, and STAT3. CONCLUSIONS: QJHF effectively attenuated the inflammatory response in severe pneumonia by inhibiting macrophage-mediated inflammation and NLRP3 inflammasome activation through TNF, NF-κB, and JAK/STAT signaling pathways.