Chronic obstructive pulmonary disease (COPD) ranks as the third most common contributor to global mortality. Oxidative stress has been recognized as a critical driver of multiple interacting mechanisms in COPD development. This research investigated the potential of oxidative stress-related genes (OSRGs) biomarkers and their potential molecular mechanisms for COPD clinical diagnosis and treatment through bioinformatics analyses. As a result, 5 hub genes, CA3, PPP1R15B, MAPT, MMP9, and ECT2, were yielded by LASSO, Boruta, and SVM-RFE, and the performance of the nomogram constructed based on hub genes was favorable. Correlation analyses between hub genes and oxidative stress biomarkers showed that MMP9 and MAPT genes had a high association with oxidative stress biomarkers. Immune cell infiltration identified follicular helper T cells, Gamma delta T cells, M0 macrophages, and CD8 T cells as significantly different in COPD. ROC of ECT2 and MMP9 showed a higher capability to discriminate COPD patients from normal samples. In addition, we collected clinical samples and analyzed the core gene expression, which revealed that the hub genes ECT2 and MMP9 had high discriminatory ability in the COPD samples. The epistasis of ECT2 and MMP9 was further verified by constructing animal models, pathological sections, qPCR, immunoblotting, immunohistochemistry, etc. The data indicated the crucial function of MMP9 in CSC-induced oxidative stress injury. Deprivation of MMP9 attenuated CSC-induced injury and promoted macrophage polarisation to M2 macrophages. MMP9 deprivation protected against CSC-induced injury, mainly related to the reduction of cell apoptosis, cell inflammation, and ROS injury in BEAS-2B. It promoted macrophage polarization from M1 to M2. In summary, we found ECT2 and MMP9 are related to oxidative stress in COPD, and MMP9 was related to cell apoptosis, cell inflammation, and ROS injury in BEAS-2B, and the macrophage polarization from M1 to M2.