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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a prevalent critical respiratory disorder caused mostly by infection and other factors. However, effective drug therapies are currently lacking. Xuanbai Chengqi Decoction (XCD), a traditional Chinese medicine (TCM) prescription, is commonly employed to treat lung diseases. It has been recommended by Chinese health authorities as one of the TCM prescriptions for COVID-19. Nonetheless, its underlying mechanism for the treatment of ALI has not been fully understood. The study aims to investigate the therapeutic effect of XCD on lipopolysaccharide (LPS) -induced ALI in mice and explore its anti-inflammatory mechanism involving pyroptosis. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was employed to identify the active compounds of XCD, and quantitative analysis of the main compounds was conducted. Male C57BL/6J mice were given different doses of XCD (4.5 and 9.0 g/kg/day) or dexamethasone (5 mg/kg/day) by oral gavage for 5 consecutive days. Subsequently, ALI was induced by injecting LPS (20 mg/kg) intraperitoneally 2 h after the last administration, and serum and lung tissues were collected 8 h later. J774A.1 cells were pretreated with different doses of XCD (100, 200, 400 μg/ml) for 12 h, then incubated with LPS (1 μg/ml) for 4 h and ATP (1 mM) for 2 h to induce pyroptosis. Supernatant and cells were collected. Moreover, J774A.1 cells were transfected with an NLRP3 overexpression plasmid for 24 h, followed by subsequent experiments with XCD (400 μg/ml). Lung histopathological changes were evaluated using hematoxylin and eosin (HE) staining. To assess the efficacy of XCD on ALI/ARDS, the levels of inflammatory factors, chemokines, and proteins associated with NLRP3 inflammasome signaling pathway were evaluated. XCD was found to ameliorate lung inflammation injury in ALI mice, and reduce the protein expression of TNF-α, IL-1β, and IL-6 in both mouse serum and J774A.1 cell supernatant. Meanwhile, XCD significantly decreased the mRNA levels of IL-1β, pro-IL-1β, CXCL1, CXCL10, TNF-α, NLRP3, NF-κB P65, and the protein expression of NLRP3, Cleaved-Caspase1, and GSDMD-N in the lung and J774A.1 cells. These effects were consistent with the NLRP3 inhibitor MCC950. Furthermore, overexpression of NLRP3 reversed the anti-inflammatory effect of XCD. The therapeutic mechanism of XCD in ALI treatment may involve alleviating inflammatory responses in lung tissues by inhibiting the activation of the NLRP3 inflammasome-mediated pyroptosis in macrophages. Schematic illustration of XCD's improvement of LPS-induced ALI in mice. LPS induces inflammation via the TLR4/NF-κB pathway, leading to the overproduction of pro-inflammatory cytokines (such as TNF-α, IL-1β, and IL-6) and promoting pro-IL-1β and NLRP3 expressions. Upon stimulation, NLRP3 protein recruits ASC and assembles Pro-Caspase1 into NLRP3 inflammasomes. Cleaved-Caspase1 cleaves pro-IL-1β into mature IL-1β. Additionally, GSDMD is cleaved into GSDMD-N by Cleaved-Caspase1, producing holes in the cell membrane and causing the release of inflammatory factors and the activation of pyroptosis, ultimately resulting in tissue damage. XCD reduces the release of inflammatory factors by inhibiting the expression of NF-κB P65 and the assembly and activation of the NLRP3 inflammasome, thereby improving the inflammatory response and providing protection against ALI. [Display omitted] • ALI/ARDS is a prevalent respiratory critical condition that lacks effective therapeutic drugs. • XCD can improve ALI inflammation. • The chemical composition and main active components of XCD were analyzed by UPLC-MS/MS. • The anti-inflammatory effect of XCD is related to NLRP3 inflammasome and pyroptosis signaling pathway. [ABSTRACT FROM AUTHOR]