BACKGROUND: Acute lung injury (ALI) is a severe inflammatory condition characterized by dysregulated immune responses and high mortality rates, with limited effective therapeutic options currently available. Panax notoginseng saponins (PNS), bioactive compounds derived from Panax notoginseng, have shown promise in mitigating lipopolysaccharide (LPS)-induced ALI. However, the molecular mechanisms underlying their therapeutic effects remain poorly understood. Given the critical role of M2-like macrophage polarization in resolving inflammation and promoting tissue repair, we investigated whether PNS exerts its protective effects in ALI by modulating this process. Furthermore, we explored the specific involvement of the signal transducer and activator of transcription 6 (STAT6) pathway in mediating these effects. METHODS: Chemical profiling of PNS was performed using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), followed by quantitative analysis of its major bioactive components via high-performance liquid chromatography (HPLC). To evaluate the therapeutic efficacy of PNS and its principal constituents, we established an ALI mouse model through intratracheal administration of LPS. Comprehensive assessments included lung field shadowing, oxygen saturation levels, pulmonary function, and systematic histopathological examination. The regulatory effects of PNS on macrophage polarization were examined in THP-1 cells and bone marrow-derived macrophages (BMDMs), with cellular phenotypes analyzed by flow cytometry. To elucidate the mechanistic role of STAT6 in PNS-mediated protection, experiments were conducted using Stat6-deficient BMDMs and Stat6 knockout mice. RESULTS: UPLC-Q-TOF-MS and HPLC identified and quantified the principal components of PNS: Notoginsenoside R1, Ginsenoside Rg CONCLUSION: This study demonstrates that PNS alleviates LPS-induced ALI by promoting STAT6-dependent M2-like macrophage polarization, highlighting its potential as a therapeutic agent for ALI. These findings provide mechanistic insights into the anti-inflammatory actions of PNS and underscore the importance of STAT6 signaling in its protective effects.