Objective To investigate the effects and mechanisms of imperatorin on mice with acute lung injury. Methods A total of 32 female BALB/c mice were randomly divided into four groups: normal control group, model group, imperatorin 30 mg/kg group, imperatorin 60?mg/kg group. Mice in imperatorin group were pretreated with imperatorin, the lung tissues of each group were collected after 7 hours of lipopolysaccharide modeling. The wet/dry weight ratio of lung was measured, the pathological changes of lung tissues in mice were observed by hematoxylin-eosin (H & E) staining, the activity of myeloperoxidase (MPO) and the reactive oxygen species (ROS) level in lung tissues of mice were measured, the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in lung tissues of mice were detected by ELISA, and the expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), nuclear factor κB (NF-κB) p65 and matrix metalloproteinase 9 (MMP-9) in lung tissues of mice were detected by Western blotting. Results Compared with normal control group, model group can lead to acute lung injury in mice, increase the lung injury score (P??0.05). Conclusion The protective effects of imperatorin on acute lung injury induced by lipopolysaccharide may be related to the inhibition of ROS and the inhibition of PI3K/Akt/NF-κB pathway mediated by ROS, and the effect of high dose group is better than that of low dose group.