Objective To investigate the changes in serum cystatin C (CysC) and plasma homocysteine (Hcy) in patients with type 2 cardiorenal syndrome and their clinical significance. Methods A retrospective analysis was performed for the clinical data of the patients with heart failure who attended our hospital from June to December, 2018, and according to the presence or absence of abnormal renal function, they were divided into heart failure group with 50 patients and cardiorenal syndrome group with 50 patients. Abnormal renal function in this study was defined as glomerular filtration rate <60 mL/min. A total of 30 healthy individuals who underwent physical examination in our hospital were enrolled as healthy control group. The changes in the indices including CysC, Hcy, and left ventricular ejection fraction (LVEF) were observed and compared between groups and patients with different conditions of cardiac function. Results The cardiorenal syndrome group and the heart failure group had significantly higher serum CysC and plasma Hcy than the healthy control group (P<0.05). The cardiorenal syndrome group had significantly higher serum CysC and plasma Hcy than the heart failure group (P <0.05). In the patients with cardiorenal syndrome, serum CysC and plasma Hcy increased with the increase in cardiac functional grading (P<0.05) and were negatively correlated with LVEF (P<0.05). The receiver operating characteristic (ROC) curve showed that CysC and Hcy had certain value in the diagnosis of cardiorenal syndrome, with an area under the ROC curve of 0.610 (95% confidence interval [CI]: 0.500-0.652) and 0.707 (95% CI: 0.596-0.812), respectively (P=0.001). Conclusion Serum CysC and plasma Hcy may help with the diagnosis of type 2 cardiorenal syndrome and can reflect disease severity to some extent.