Introduction: Sepsis is a deleterious, systemic inflammatory response to infection. Despite advances in treatment, the mortality rate of sepsis remains high. Recently, a new definition has been punished as life-threatening organ dysfunction caused by a dysregulated host response to infection in sepsis-3. Here, we hypothesized that metabolite changes in plasma could be used to study sepsis and patients complicated by organ dysfunction. Methods: Plasma samples from 31 patients with sepsis and 23 healthy individuals of matching age, Body Mass Index(BMI), and gender were collected. We used gas chromatography-mass spectrometry (GC-MS) for global metabolic profiling. Then, according to organ dysfunction, plasma samples of sepsis patients were regrouped into acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), sepsis-induced myocardial dysfunction (SIMD), and acute hepatic ischemia(AHI). The other samples were regrouped as controls. The predicted metabolic pathways were from KEGG data. Student's t-test was employed to identify the metabolites and predicted metabolic pathways that significantly differed between septic patients and healthy controls. Results: A total of 222 metabolites were detected, which included 124 metabolites that statistically differed between individuals with sepsis and the controls. In addition, approximately 158 metabolic pathways were predicted, of which 74 were significant. Further subgroup analysis identified seven metabolites in AKI, three metabolites in ARDS, seven metabolites in SIMD, and four metabolites in AHI that were significantly different in metabolite. The results showed that the septic samples exhibited extensive changes in amino acids, fatty acids, and TCA-cycle products. In addition, three metabolic pathways — namely, energy metabolism, amino acid metabolism, and lipid metabolism—were downregulated in sepsis patients. Some metabolites such as phenylalanine and glutamine may be the crucial metabolites that are involved in the progression from sepsis to MODS.. Conclusions: GC-MS detection and metabolomic analysis of serum samples of sepsis patients resulted in the identification of metabolites and metabolic pathways related to sepsis and sepsis-associated organ dysfunction. Three important metabolic pathways (energy metabolism, amino acid metabolism, and lipid metabolism) were downregulated in sepsis patients. These findings may serve as novel clinical evidence for the dysregulated internal environment, particularly involving energy metabolism that results in sepsis. Funding Statement: This study was supported by National Natural Science Foundation grants of China (81873928, to FX, 81801894 to SH-L, 81873604 to XH-L), Basic science and cutting-edge technology research projects of Chongqing Science & Technology Commission (cstc2016jcyjA0005, to FX),Special fund of social undertakings and people’s livelihood guarantee of Chongqing science and technology commission(cstc2017shmsA130072, to FX), the Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJ1702034, to FX), Medical research project of Chongqing City Health and Family Planning committee(2017ZDXM007, to FX) and Chinese medicine science and technology project of Chongqing City Health and Family Planning committee(ZY201702071, to FX) Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by the Ethics Committees of the First Affiliated Hospital of Chongqing Medical University. (2016-34)