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Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening pulmonary disorders with high mortality rates, and effective treatments are currently lacking. Secoisolariciresinol diglucoside (SDG), a plant lignan derived from flaxseed, possesses anti-inflammatory and antioxidative activities. However, the underlying mechanisms by which SDG ameliorates ALI remain incompletely understood. This study aimed to investigate whether SDG alleviates ALI by modulating the NF-κB/NLRP3 signaling pathway. For the in vivo study, ALI was induced in mice through intranasal administration of LPS. Key indicators included lung histopathological changes, wet/dry weight ratio (W/D), protein concentration in bronchoalveolar lavage fluid (BALF), oxidative stress markers (MDA, SOD, CAT), the expression of inflammatory cytokines and chemokines (IL-1β, IL-18, TNF-α, CCL2), and the level of NF-κB/NLRP3 pathway-related proteins. In vitro experiments using LPS-stimulated RAW264.7 further explored the effects of SDG on the NF-κB/NLRP3 pathway. SDG significantly mitigated LPS-induced lung histopathological damage and nasal mucosal injury, reduced lung W/D ratio and BALF protein, and suppressed oxidative stress. Moreover, SDG downregulated pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) and macrophage infiltration. It also decreased the expression of N-κB/NLRP3 pathway-related proteins. In vitro experiments further confirmed that SDG inhibited the NF-κB/NLRP3 pathway. SDG effectively alleviates LPS-induced ALI through its antioxidant, anti-inflammatory, and NF-κB/NLRP3 pathway-inhibiting properties, providing experimental evidence for its potential as a therapeutic agent for ALI.