Chronic obstructive pulmonary disease (COPD) is a worldwide public health challenge because of its high prevalence and related disability and mortality; however, the pathogenesis of COPD remains unknown. The aim of this study was to reveal the critical proteins involved in the pathogenesis of COPD. This study used high-resolution liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), in combination with quantitative 6-plex tandem mass tag labeling, to profile protein changes in lung tissues from patients with COPD and healthy donors. Western blot analyses were used to validate the proteomic data. A total of 4976 proteins were identified and analyzed. One-hundred and seventy-three proteins were found significantly changed, with 118 proteins downregulated and 55 proteins upregulated. Gene ontology analysis and protein-protein interaction networks demonstrated that the changed proteins, especially down-regulated proteins, were involved in platelet and macrophage activation. Our results indicated that abnormal platelet activation caused by down-regulation of GP6, PF4, and THBS1 contributes to the hemostasis disorders, while dysfunction of alveolar macrophages in efferocytosis, as a result of down-regulation of CD163 and MARCO, caused the failure of resolution of inflammation, and thus cause COPD.