Objective To observe the protective effect of salidroside on the mouse model of hyperoxic lung injury and to explore its mechanism of action. Methods Fifty C57BL/ 6 mice were randomly divided into normal control group, model group, positive control group (10 mg / kg dexamethasone), high-dose salidroside group (50 mg / kg) and low-dose salidroside group (25 mg / kg). All mice except those in the normal control group were exposed to hyperoxia for 3 days to establish a model of hyperoxic lung injury. The wet / dry weight (W/ D) ratio and partial pressure of arterial oxygen (PaO₂) of the lung tissues were measured in each group of mice. Hematoxylin-eosin staining was used to observe the pathological changes in the lung tissues of the mice. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the content of TNF-α, IL-1β, IL-6, MDA and SOD activity of lung tissues. Western blot and real-time quantitative polymerase chain reaction were used to detect Notch1, HERP, and HES1 protein and mRNA expression levels. Results Compared with the normal control group, the W/ D value of lung tissues in the model group increased, PaO₂ level decreased, lung tissue structure was disordered, alveolar wall thickened, inflammation infiltration and collagen deposition were obvious, TNF-α, IL-1β, IL-6 content of the lung tissues increased, SOD activity decreased, MDA content increased, Notch1, HERP, HES1 mRNA and protein expression decreased (P<0.05). Compared with the model group, the W/ D value of the lung tissues of the mice in salidroside high-dose group and the low-dose group was significantly reduced, and the PaO₂ level was significantly increased. The lung tissue alveolar structure of the mice in the high-dose salidroside group was basically normal and inflammation cells and collagen deposits were less, the inflammatory factors TNF-α, IL-1β, IL-6 content of the lung tissues decreased, SOD activity increased, MDA content decreased, and the expression levels of Notch1, HERP, HES1 protein and mRNA in lung tissues increased (P<0.05). Compared with the positive control group, the effect of high-dose salidroside was not statistically different (P>0.05). Conclusions Salidroside has a protective effect against hyperoxia- induced lung injury in mice, and its mechanism of action may be related to changes in the expression of the Notch signaling pathway.