BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, alveolar barrier dysfunction, edema, and dysregulated alveolar macrophage-mediated pulmonary inflammation. Despite advancements in treatment strategies, the mortality rate in patients with ARDS remains high, ranging from 40-60 %. Current approaches are limited to supportive care, necessitating the exploration of effective therapeutic options such as suppressing broad inflammatory responses. Although Cirsium japonicum leaves possess anti-inflammatory properties, their specific effects on ARDS have not yet been investigated. METHODS: The anti-inflammatory activity of Cirsium japonicum extract (CJE) was investigated in a lipopolysaccharide (LPS)-induced ARDS model. RESULTS: CJE significantly attenuated LPS-induced lung injury, including reduced alveolar wall thickness, inflammatory cell infiltration, proteinaceous debris, and hyaline membranes. Moreover, CJE repressed infiltration of inflammatory cells and pro-inflammatory gene expression in bronchoalveolar lavage fluid. Concordantly, CJE mitigated alveolar macrophage activation, which consequently reduced neutrophil chemoattractic infiltration. Additionally, CJE suppressed NLRP3 and HIF1α expression in the lungs of the ARDS mouse. Similarly, LPS-induced NLRP3 and HIF1α pathway-associated inflammatory and glycolytic gene expressions significantly diminished by CJE in murine alveolar macrophage cell line, MH-S cells, and bone marrow-derived macrophages. CONCLUSION: CJE suppressed multiple inflammatory responses through the regulation of NLRP3 and HIF1α signaling-related gene expression in macrophages of LPS-induced ARDS mice. These results suggest that CJE has therapeutic potential for treating patients with ARDS via macrophage regulation.