Bronchopulmonary dysplasia (BPD) remains a major complication and accounts for high morbidity and mortality of preterm infants. The present study aimed to identify the key genes in the development of BPD and to provide some new insights into the pathogenesis of BPD. The GSE108754 dataset was downloaded from Gene Expression Omnibus database containing 5 samples of BPD patients and 6 of non-BPD infants. The differentially expressed genes (DEGs) between BPD and non-BPD patients were identified by R software. The pathway and function enrichment analyses were performed through Database for Annotation Visualization and Integrated Discovery website. The protein-protein interaction network for DEGs was established by Cytoscape software and the most highly connected module was selected through MCODE plugin. Furthermore, the clinical sample verification among 25 BPD patients and 10 non-BPD infants was carried out in our center. Finally, based on the results above, the gene set enrichment analysis focusing on CD74 upregulated status was employed. Totally, 189 DEGs including 147 upregulated genes and 42 downregulated genes between BPD and non-BPD patients were screened out. The pathway and function enrichments revealed these DEGs were mainly enriched in asthma, intestinal immune network for IgA production, antigen processing and presentation and immune response. Thirteen DEGs (CD74, HLA-DMA, HLA-DRA, HLA-DMB, HLA-DOB, HLA-DQA1, HLA-DRB5, HLA-DPA1, HLA-DOA, HLA-DPB1, HLA-DQB2, HLA-DQA2, and HLA-DQB1) were determined as hub genes. The mRNA expression levels of the 13 hub genes were tested by quantitative real-time polymerase chain reaction among our clinical samples. Eventually, CD74 was confirmed to be the most significant highly expressed in BPD samples (P < .001) and its expression level was negatively correlated with gestational age (r = -0.653) and birth weight (r = -0.675). The gene set enrichment analysis results showed the gene sets associated with lupus erythematosus, viral myocarditis, immune network for IgA production, graft versus host disease, cell adhesion molecules and so no were differentially enriched with the phenotype of high-expression CD74. In conclusion, CD74 may serve to predict the BPD development and provide a new therapeutic target for BPD.