Background: Lung cancer is one of the malignancies exhibiting the fastest increase in morbidity and mortality, but the cause is not clearly understood. The goal of this investigation was to screen and identify relevant biomarkers of lung cancer. Methods: Publicly available lung cancer data sets, including GSE40275 and GSE134381, were obtained from the GEO database. The repeatability test for data was done by principal component analysis (PCA), and a GEO2R was performed to screen differentially expressed genes (DEGs), which were all subjected to enrichment analysis. Protein-protein interactions (PPIs), and the significant module and hub genes were identified via Cytoscape. Expression and correlation analysis of hub genes was done, and an overall survival analysis of lung cancer was performed. A receiver operating characteristic (ROC) curve analysis was performed to test the sensitivity and specificity of the identified hub genes for diagnosing lung cancer. Results: The repeatability of the two datasets was good and 115 DEGs and 10 hub genes were identified. Functional analysis revealed that these DEGs were associated with cell adhesion, the extracellular matrix, and calcium ion binding. The DEGs were mainly involved with ECM-receptor interaction, ABC transporters, cell-adhesion molecules, and the p53 signaling pathway. Ten genes including COL1A2, POSTN, DSG2, CDKN2A, COL1A1, KRT19, SLC2A1, SERPINB5, DSC3, and SPP1 were identified as hub genes through module analysis in the PPI network. Lung cancer patients with high expression of COL1A2, POSTN, DSG2, CDKN2A, COL1A1, SLC2A1, SERPINB5, and SPP1 had poorer overall survival times than those with low expression (p #60;0.05). The CTD database showed that 10 hub genes were closely related to lung cancer. Expression of POSTN, DSG2, CDKN2A, COL1A1, SLC2A1, SERPINB5, and SPP1 was also associated with a diagnosis of lung cancer (p#60;0.05). ROC analysis showed that SPP1 (AUC = 0.940, p = 0.000*, 95%CI = 0.930-0.973, ODT = 7.004), SLC2A1 (AUC = 0.889, p = 0.000*, 95%CI = 0.791-0.865, ODT = 7.123), CDKN2A (AUC = 0.730, p = 0.000*, 95%CI = 0.465-1.000, ODT = 6.071) were suitable biomarkers. Conclusions: Microarray technology represents an effective method for exploring genetic targets and molecular mechanisms of lung cancer. In addition, the identification of hub genes of lung cancer provides novel research insights for the diagnosis and treatment of lung cancer.