Neutrophils have crucial roles in defensing against infection and adaptive immune responses. This study aimed to investigate the genetic mechanism in neutrophils in response to sepsis-induced immunosuppression.The GSE64457 dataset was downloaded from the Gene Expression Omnibus database and the neutrophil samples (D3-4 and D6-8 post sepsis shock) were assigned into two groups. The differentially expressed genes (DEGs) were identified. The Short Time-series Expression Miner (STEM) clustering analysis was conducted to select the consistently changed DEGs post sepsis shock. The overlapping genes between the DEGs and the deposited genes associated with immune, sepsis, and immunosuppression in the AmiGO2 and Comparative Toxicogenomics Database were screened out and used for the construction of the protein-protein interaction (PPI) network. The expression of several hub genes in sepsis patients was validated using the PCR analysis. The drugs targeting the hub genes and the therapy strategies for sepsis or immunosuppression were reviewed and used to construct the drug-gene-therapy-cell network to illustrate the potential therapeutic roles of the hub genes.A total of 357 overlapping DEGs between the two groups were identified and were used for the STEM clustering analysis, which generated four significant profiles with 195 upregulated (including annexin A1, ANXA1; matrix metallopeptidase 9, MMP9; and interleukin 15, IL-15) and 151 downregulated DEGs (including, AKT1, IFN-related genes, and HLA antigen genes). Then, a total of 34 of the 151 downregulated DEGs and 39 of the 195 upregulated DEGs were shared between the databases and above DEGs, respectively. The PPI network analysis identified a downregulated module including IFN-related genes. The deregulation of DEGs including AKT1 (down), IFN-inducible protein 6 (IFI6, down), IL-15 (up), and ANXA1 (up) was verified in the neutrophils from patients with sepsis-induced immunosuppression as compared with controls. Literature review focusing on the therapy showed that the upregulation of IL-15, IFN, and HLA antigens are the management targets. Besides, the AKT1 gene was targeted by gemcitabine.These findings provided additional clues for understanding the mechanisms of sepsis-induced immunosuppression. The drugs targeting AKT1 might provide now clues for the management strategy of immunosuppression with the intention to prevent neutrophil infiltration.