Objective: To investigate the protective effects of the ubiquitin proteasome inhibitor MG-132 on p38 signaling pathway and apoptosis in lung injury induced by hyperoxia. Methods: Twenty-six SD rats were randomly divided into 4 groups: normal control group (n = 5), MG-132 control group (n = 5), hyperoxia group (n = 8) and MG-132 hyperoxia group (n = 8). Hyperoxia lung injury rat models were established, and proteasome inhibitor (0.5 mg/kg) was intraperitoneally injected in control group and MG-132 hyperoxia group once daily. The resected lungs were histopathologically examined, and cell apoptosis and expression of ubiquitin and p38 were detected by TUNEL and immunohistochemistry, respectively. Results: After hyperoxia exposure, there were edema and inflammatory cell infiltration in the lung tissues of SD rats. The apoptosis index and expression of p38MAPK of hyperoxia group were higher than those of normal control group and MG-132 hyperoxia group (P < 0.05 or P < 0.01). Conclusion: High oxygen can induce cell apoptosis and may activate p38MAPK signaling pathway. The proteasome inhibitor MG-132 can reduce the lung injury induced by hyperoxia and inhibit P38MAPK signaling pathway.