Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) may be related to the increase of chronic kidney disease and mortality in critically ill patients, so developing potential biomarkers is particularly important for disease prediction and early diagnosis. The purpose of this study was to investigate the alteration profiles of plasma metabolome and the possible links with urinary metabolome in patients with CSA-AKI. Methods: Non-targeted metabolomics was performed on plasma samples collected from groups of patients with CSA-AKI at different time points, including Before_AKI (uninjured kidney), AKI_Day1 (injured kidney) and AKI_Day14 (recovered kidney). The differential plasma metabolites associated with CSA-AKI were screened out using multivariate and univariate statistical methods, and altered metabolic pathways were identified by examining the Kyoto Encyclopedia of Genes and Genomes database. After receiver operating characteristic analysis to obtain potential biomarkers, the differential plasma metabolites with Level 1 were used for correlation analysis and metabolomic interplay with urinary metabolome. Results: Nearly 1750 plasma metabolites were identified through bioinformatics methods at Annotation Levels 1-3. The plasma metabolome of injured kidney can be well separated from the plasma metabolomes of uninjured or recovered groups, but the plasma samples from the AKI_Day14 and Before_AKI groups cannot be distinguished using statistical analysis. Compared with the uninjured kidney group, the patients with CSA-AKI displayed dramatic changes in plasma metabolism, particularly for amino acid metabolism. As for the potential biomarkers with Level 1 identification in the plasma metabolome, carnitines and amino acid metabolites exhibited a significant positive correlation, while carnitines and organic acids in plasma also involved in the metabolomic interplay with urinary metabolome. Conclusions: Plasma metabolite disorder was observed in patients with CSA-AKI due to ischaemia and medical treatment, and the recovered patients’ systemic status were able to return to normal. This work provides data on plasma metabolite markers on CSA-AKI and possible link to urinary metabolome.