Background: Guben Zhike decoction (GBZKD) is derived from the experience of Professor Enxiang Chao, an esteemed master of Chinese medicine, while treating chronic obstructive pulmonary disease (COPD). GBZKD reinforces the healthy qi and consolidates defensive qi. This study explored the efficacy and potential mechanism of action of GBZKD in a COPD mouse model using proteomics.Methods: A COPD mouse model was established through cigarette smoke exposure and intranasal lipopolysaccharide administration. The model was verified through lung function test and lung histo-pathological observation. Label-free quantitative proteomics was used to detect the lung tissue proteins of mice from the GBZKD, COPD, and control groups. Results: GBZKD markedly improved the lung function and associated pathological conditions in the COPD mouse model. Proteomic analysis identified 4316 proteins, of which 3696 were quantitative proteins. We highlighted 287 and 184 proteins with significant regulatory roles in the lung tissues of COPD mice and GBZKD-treated mice, respectively. These proteins participated in multiple functions, including complement/coagulation cascade, immune response, and metabolic pathways. Conclusion: GBZKD exhibits multitarget and multipathway therapeutic effects in a COPD mouse model.