Background: Epigenetic modifications, such as chromatin remodeling, are critical in regulating sepsis immunity. Identifying differentially expressed chromatin remodeling-related genes (DE-CRRGs) may reveal potential therapeutic targets for sepsis. Methods: Using the GSE65682 dataset, we identified DE-CRRGs between sepsis and normal groups. Least absolute shrinkage and selection operator (LASSO) regression, support vector machine (SVM), and random forest algorithms were applied to screen hub genes. Immune cell infiltration was analyzed using cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT), and ceRNA regulatory and co-expression networks were constructed. Potential drugs were predicted using the Drug Gene Interaction Database. Results: We identified 17 DE-CRRGs and six hub genes: spondin 2 (SPON2), transglutaminase 2 (TGM2), matrix metalloproteinase 9 (MMP9), DNA Methyltransferase 1 (DNMT1), lymphocyte antigen 96 (LY96), and forkhead box protein 1 (FOXO1). These genes were significantly correlated with immune cell infiltration, particularly activated natural killer (NK) cells, cluster of differentiation (CD)8 T cells, and plasma cells. The hub genes were involved in interleukin-18 signaling and cell development. Additionally, 62 potential drugs for sepsis treatment were predicted. Conclusions: These findings provide insights into the epigenetic regulation of sepsis and suggest potential therapeutic targets and drugs for intervention.