This study explores the significant differential expression of peptides in sepsis patients compared to healthy controls and those with common infections using plasma peptidomics analysis. Blood samples were collected from 10 pediatric sepsis patients admitted to Hunan Children's Hospital in 2021, along with 20 age- and sex-matched healthy controls and 5 children with common infections. Differential peptide precursor proteins underwent GO and KEGG pathway enrichment analyses and protein-protein interaction analysis using the STRING database. A total of 3149 endogenous peptides corresponding to 480 precursor proteins were identified. Compared to the healthy group, the sepsis group exhibited 1113 differential peptides, with 880 upregulated and 233 downregulated. Compared to the common infection group, the sepsis group showed 181 upregulated and 86 downregulated peptides. These differences were primarily in humoral immune response and complement and coagulation cascades. The peptide RSFFSFLGEA, associated with the precursor protein SAA1, had the highest LogFC values between sepsis and healthy groups, and sepsis and common infection groups, with values of 6.828 and 5.580, respectively. This study reveals specific changes in peptide expression in sepsis patients' plasma, particularly significant alterations in peptides related to SAA1, complement C3, HB, and HP. These peptides are involved in acute inflammatory response, complement system, and free hemoglobin pathways, indicating their crucial roles in sepsis pathology. These findings provide new insights into the mechanisms of sepsis and suggest potential applications of these peptides in sepsis diagnosis and treatment, aiming to improve early diagnosis and therapeutic outcomes.