INTRODUCTION: The plasma lipidome has emerged as an important indicator for assessing host metabolic and immune status in sepsis. While previous studies have largely examined specific lipid class changes in adults sepsis, comprehensive investigations into plasma lipidomic alterations in pediatric sepsis are limited. This study aimed to characterize the plasma lipidome in pediatric sepsis using a metabolomics-based exploratory approach, providing insights into pathophysiological mechanisms and potential biomarkers. METHODS: A retrospective study was conducted on pediatric patients with sepsis admitted to the pediatric intensive care unit (PICU). Untargeted lipidomics analysis using ultra-performance liquid chromatography coupled with Orbitrap mass spectrometry (UPLC-Orbitrap) was performed to compare metabolomic profiles between non-infected control patients and sepsis patients. RESULTS: Compared to controls, plasma lipid levels in sepsis patients decreased by 33.3%, increased by 20.2%, and remained unchanged in 46.5% of cases. A total of 1,257 differential lipids were identified in sepsis patients, with 24 lipids showing significant associations with pSOFA scores. In the recovery and deterioration subgroups, 186 differential lipids were identified, with triglyceride (TG) representing the highest proportion at 16.4%. Notably, 15 lipids with significant statistical differences were identified as differential lipid species through a comparison of those associated with pSOFA scores and those linked to sepsis prognosis. Fatty acid (FA) levels were significantly elevated in the sepsis group compared to controls, with arachidonic acid (FA(20:4)) showing the most significant increase (P < 0.001). CONCLUSION: Alterations in plasma lipid profiles among children with sepsis reflect disease severity, systemic inflammatory responses, and sepsis prognosis. These findings underscore the prognostic potential of lipidomics and its value in understanding sepsis pathophysiology.