Background and purpose. Sakuranetin is the main isolate flavonoid from Baccharis retusa (Asteraceae) leaves and exhibits anti-inflammatory and anti-oxidative activities. Acute respiratory distress syndrome is an acute failure of the respiratory system for which effective treatment is urgently necessary. This study investigated the preventive and therapeutic effects of sakuranetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Experimental approach. Animals were treated with intranasal sakuranetin 30 minutes before or 6 hours after instillation of LPS. Twenty-four hours after ALI was induced, lung function, inflammation, macrophages population markers, collagen fiber deposition, the extent of oxidative stress, and the expression of MMP-9, TIMP-1 and NF-kB were evaluated. Key results. The animals began to show lung alterations six hours after LPS instillation and these changes persisted until 24 hours after LPS administration. Preventive and therapeutic treatment with sakuranetin reduced the neutrophils in the peripheral blood and in the bronchial alveolar lavage. Sakuranetin treatment also reduced macrophages populations, particularly that of M1-like macrophages. In addition, sakurnaetin treatment reduced KC (IL-8 homologue) and NF-B levels, collagen fiber formation, MMM-9 and TIMP-1-positive cells, and oxidative stress in lung tissues compared with LPS animals treated with vehicle. Finally, sakuranetin treatment also reduced total protein, and the levels of TNF-α and IL-1β in the lung. Conclusions and Implications. This study shows that sakuranetin prevented and reduced pulmonary inflammation induced by LPS. Because sakuranetin modulates oxidative stress, the NF-kB pathway and lung function, it may constitute a novel therapeutic candidate to prevent and treat ALI.