Objective To explore the mechanism of extracellular signal ⁃ regulated protein kinase 1/2 （ERK1/2）inhibitor U0126 on airway hypersecretion of mucin 5ac（muc5ac）protein in chronic obstructive pulmo⁃ nary disease（COPD）mice. Methods The pulmonary function indexes，interleukin 4（IL ⁃4）and interferon γ （IFN⁃γ）levels of each group of mice after 7 days of intervention with different drugs were detected.HE staining to observe the pathological changes of lung tissue. RT⁃qPCR was used to detect the expression levels of muc5ac and ERK1/2 mRNA in lung tissues. Western blotting was used to detect the expression levels of muc5ac，ERK1/2，and p⁃ERK1/2 proteins in lung tissue. Results Compared with the model group，the levels of FEV0.3，FVC，FEV0.3/ FVC and IL⁃4 in the inhibitory drug group and the western drug group were increased，whereas the levelsof IFN⁃γ， muc5acmRNA，and the protein expression levels of muc5ac and p⁃ERK1/2 were decreased（P < 0.05）. The patho⁃ logical changes of lung tissue improved. Conclusion ERK1/2 inhibitors can reduce the expression of muc5ac by inhibiting the ERK1/2 signaling pathway and improve the symptoms of COPD.