Background: To investigate the effect of Rehmannia glutinosa polysaccharide (RGP) in rats with chronic renal failure. Materials and Methods: In this study, we established a rat model of adenine-induced chronic renal failure. Hemoglobin (Hb), red blood cells (RBCs), total protein (TP), serum albumin (ALB), blood urea nitrogen (BUN), cystatin C (Cys C), and serum creatinine anhydride (SCA) were detected in the blood samples of rats. Hematoxylin and eosin staining was used to observe the pathological changes. Immunohistochemical was used to detect the protein expression of hypoxia-inducible factor (HIF)-2α, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) and calculate the value of microvessel density (MVD) in renal tissues. M1001 and GPRRP + PT2385 groups were added to further validate the mechanism of RGP. Results: In the case of rats with chronic renal failure, GPRRP and EPO contributed to the repairment of renal tissue. The level of Hb, TP, and ALB, as well as RBC counts was significantly increased, and the renal function indexes, including BUN, SCA, and Cys C, were significantly decreased, and HIF-2α, EPO, VEGF, and MVD were significantly increased. The effects observed in M1001 group was similar to those in GPRRP group, but compared with GPRRP + PT2385 group, the biochemical indicators and renal function indexes were significantly decreased, which means HIF-2α inhibitor antagonized the protective effect of RGP. Conclusion: RGP played an essential role in repairing the renal injury in rats with chronic renal failure. The therapeutic mechanism of action may be related to the activation of HIF-2α, thereby increasing the expression of EPO and VEGF and then reducing renal anemia and renal tissue damage.