BACKGROUND AND PURPOSE Acute lung injury (ALI) is a challenging clinical syndrome that manifests as an acute inflammatory response. The NLRP3 inflammasome is involved in the development of ALI. Yadanzigan (YDZG) is isolated from Brucea javanica (Linn.) Merr (Simaroubaceae) (Yadanzi), an anti-inflammatory herb widely used in traditional Chinese medicine. However, the anti-inflammatory effect and mechanism of YDZG on ALI have not been reported. ¬ EXPERIMENTAL APPROACH The in vitro anti-inflammatory effect and mechanism of YDZG were investigated through ELISA, qRT-PCR, Western blotting, and immunoprecipitation assay. ALI model was established by non-invasive intratracheal instillation of LPS into lung of mice. The therapeutic effect of YDZG on ALI was assessed by changes in histopathological and pro-inflammatory markers. The underlying mechanisms were investigated by Western blotting on lung tissue. KEY RESULTS YDZG specifically inhibits NLRP3 inflammasome activation. In cultured macrophages, YDZG attenuated the NF-κB pathway and mitochondrial reactive oxygen species production and enhanced TRIM31 expression to inhibit NLRP3 inflammasome activation. YDZG also ameliorated LPS-induced acute lung injury in mice by inhibiting the expression of NLRP3. CONCLUSIONS AND IMPLICATIONS This study uncovers the underlying mechanism and the anti-inflammatory activity of YDZG in ALI, suggesting that NLRP3 inflammasome may be an effective target of the treatment with ALI.