Genomic abnormality is a crucial factor for lung cancer development. This study used bioinformatics analysis to explore the hub genes involved in lung adenocarcinoma. The GeneCards, Comparative Toxicogenomics Database (CTD), and DISEASES databases were used to screen the genes associated with lung adenocarcinoma. The hub genes were then identified using WebGestalt. The Cancer Genome Atlas (TCGA), UALCAN, and the Human Protein Atlas (HPA) were used to validate the expression of hub genes. The predictive effects of hub genes on the risk of lung adenocarcinoma were evaluated using receiver operating characteristic (ROC) curve analysis. The Tumor-Immune System Interaction Database (TISIDB) was used to estimate the correlation between hub genes and immune infiltration. A total of 21 genes were defined as common genes associated with lung adenocarcinoma, and from these, AKT1, CD44, and CDKN2A were identified as hub genes. Significant differences in the hub gene mRNA and protein expression were observed between lung adenocarcinoma samples and normal samples derived from the TCGA and UALCAN databases. The area under the ROC curve (AUC) for AKT1, CD44, and CDKN2A in predicting lung adenocarcinoma risk was 0.847, 0.880, and 0.805, respectively, with sensitivity of 89.8%, 93.2%, and 94.9%, respectively. TISIDB analysis indicated that AKT1, CD44, and CDKN2A expression had a strong relationship with immune infiltration in lung adenocarcinoma. These hub genes, AKT1, CD44, and CDKN2A, may represent tumor biomarkers that may contribute to the understanding, diagnosis, and treatment of lung adenocarcinoma.