Objective. The purpose of the present study is to screen the hub genes associated with sepsis, comprehensively understand the occurrence and progress mechanism of sepsis, and provide new targets for clinical diagnosis and treatment of sepsis. Methods. The microarray data of GSE9692 and GSE95233 were downloaded from the Gene Expression Omnibus (GEO) database. The dataset GSE9692 contained 29 children with sepsis and 16 healthy children, while the dataset GSE95233 included 102 septic subjects and 22 healthy volunteers. Differentially expressed genes (DEGs) were screened by GEO2R online analysis. The DAVID database was applied to conduct functional enrichment analysis of the DEGs. The STRING database was adopted to acquire protein-protein interaction (PPI) networks. Results. We identified 286 DEGs (217 upregulated DEGs and 69 downregulated DEGs) in the dataset GSE9692 and 357 DEGs (236 upregulated DEGs and 121 downregulated DEGs) in the dataset GSE95233. After the intersection of DEGs of the two datasets, a total of 98 co-DEGs were obtained. DEGs associated with sepsis were involved in inflammatory responses such as T cell activation, leukocyte cell-cell adhesion, leukocyte-mediated immunity, cytokine production, immune effector process, lymphocyte-mediated immunity, defense response to fungus, and lymphocyte-mediated immunity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that sepsis was connected to bacterial and viral infections. Through PPI network analysis, we screened the most important hub genes, including ITK, CD247, MMP9, CD3D, MMP8, KLRK1, and GZMK. Conclusions. In conclusion, the present study revealed an unbalanced immune response at the transcriptome level of sepsis and identified genes for potential biomarkers of sepsis, such as ITK, CD247, MMP9, CD3D, MMP8, KLRK1, and GZMK.