BACKGROUND: Severe acute pancreatitis associated with acute lung injury (SAP-ALI) is a critical condition with a high mortality rate. Investigating the pathogenesis of SAP-ALI and developing effective treatments are urgently needed. Chaihuang Qingfu Pills (CHQF), a traditional Chinese medicine modified from Qingyi Decoction, has been approved for treating acute pancreatitis (AP). However, its role in SAP-ALI and the underlying mechanisms remain unclear. METHODS: 92 AP patients were enrolled to observe the protective effect of CHQF on AP-ALI. L-arginine was used to establish the SAP-ALI animal model. UHPLC-MS/MS was used to identify the components of CHQF absorbed into the serum. Transcriptomics analysis, network pharmacology, and proteomics approaches were used to explore the underlying molecular mechanism. In vivo and in vitro experiments were conducted to validate the relevant findings. RESULTS: Clinical data indicated CHQF reduced the incidence of ALI from 58.33% to 36.36% in AP patients. Animal experiments demonstrated that CHQF decreased mortality, attenuated organ damage, inhibited systemic inflammation and reduced pathological injury in SAP mice. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified 146 SAP-related differentially expressed genes (DEGs) from the GSE194331 dataset. UHPLC-MS/MS analysis acquired 26 components absorbed into the blood and 271 associated therapeutic targets. Integrated analysis obtained 52 core targets of CHQF in treating SAP. Proteomic analysis identified 216 proteins associated with CHQF treatment in SAP-ALI. Joint analysis found that MMP9 and NLRP3 were the only common targets. Both in vivo and in vitro experiments confirmed that CHQF reduced the levels of MMP9 and NLRP3 and inhibited pyroptosis in alveolar macrophages (AMs) under SAP conditions. Moreover, the MMP9 inhibitor reduced NLRP3 expression and suppressed AMs pyroptosis. CONCLUSION: CHQF exerted a protective role in SAP-ALI by inhibiting macrophage pyroptosis through the MMP9-NLRP3 pathway, providing a novel therapeutic strategy for SAP-ALI.