Lipidomics has been applied in the identification and quantification of molecular lipids within an organism, and to provide insights into mechanisms in clinical medicine. Sepsis is a major systemic inflammatory syndrome and the liver here is a potential target organ for dysfunctional response. However, the study of alterations in global lipid profiles associated with sepsis-induced liver injury is still limited. In this work, we set out to determine alterations of lipidomics profiles in a rat model of sepsis-induced liver injury using an untargeted lipidomics strategy. Liquid chromatography coupled with mass spectrometry in conjunction with multivariate data analysis and pathway analysis were used to acquire a global lipid metabolite profile. Meanwhile, biochemistry index and histopathological examinations of the liver were performed to obtain auxiliary measurements for determining the pathological changes associated with sepsis-induced liver injury. Eleven lipid metabolites and two metabolic pathways were discovered and associated with sepsis-induced liver injury. The results indicated that various biomarkers and pathways may provide evidence for and insight into lipid profile alterations associated with sepsis-induced liver injury, and hence pointed to potential strategic targets for clinical diagnosis and therapy in the future.