Backgroubd: Septic cardiomyopathy is a potentially fatal complication of sepsis. In this study, transcriptomic and proteomic analyses of the sera of sepsis patients were performed to identify the underlying pathological mechanism as well as potential targets for the treatment of septic cardiomyopathy. Methods: This study presents a prospective single-center investigation into the progression of sepsis patients to septic cardiomyopathy during their ICU admission. A total of 50 patients were enrolled, categorized into two groups: sepsis with cardiomyopathy (25 cases) and sepsis alone (25 cases). To elucidate the biological significance of identified proteins, we employed co-expression network analysis. Furthermore, leveraging proteomic and transcriptomic data, we constructed molecular networks to elucidate the interactions among pivotal molecules. This approach aims to enhance the clarity and logical coherence of our data interpretation, thereby strengthening the overall argumentation of the study. Results: A total of 216 differentially expressed proteins (| Fold change > 1.5 and P-value < 0.05) were identified in the proteomic analysis. Transcriptome association analysis showed that two proteins were co-downregulated in patients with septic cardiomyopathy, with IL-27B associated with the immune response. KEGG pathway enrichment showed that IL-27B was involved in the cytokine-cytokine receptor-interaction signaling pathway. Conclusion: Comprehensive transcriptomic and proteomic analyses identified specific changes in protein expression in septic cardiomyopathy, most of which were associated with inflammation-related pathways and amino acid metabolism. These findings thus describe the pathological features and pathways associated with septic cardiomyopathy and identify potential therapeutic targets.