Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic patients and 71 non-septic elderly participants were enrolled, and their plasma samples were collected for transcriptomics (RNA-seq) and metabolomics (NMR and GC-MS) analyses, which are both increasingly being utilized to discover key molecular changes and potential biomarkers for various diseases. Protein-protein interaction (PPI) analysis was subsequently performed to assist cross-platform integration. Real time polymerase chain reaction (RT-PCR) was used for validation of RNA-seq results. For further understanding of the mechanisms, cecal ligation and puncture (CLP) experiment was performed both in young and middle-aged rats, which were subjected to NMR-based metabolomics study and validated for several key inflammation pathways by western blot. Comprehensive analysis of data from the two omics approaches provides a systematic perspective on dysregulated pathways that could facilitate the development of therapy and biomarkers for elderly sepsis. Additionally, the metabolites of lactate, arginine, histamine, tyrosine, glutamate and glucose were shown to be highly specific and sensitive in distinguishing septic patients from healthy controls. Significant increases of arginine, trimethylamine N-oxide and allantoin characterized elderly patient incurred sepsis. Further analytical and biological validations in different subpopulations of septic patients should be carried out, allowing accurate diagnostics and precise treatment of sepsis in clinic.