This study aimed to investigate the efficacy of roxadustat combined with recombinant human erythropoietin (rhEPO) on renal anemia during maintenance hemodialysis (MHD) in chronic kidney disease (CKD) patients, and explored the underlying mechanisms. Twenty CKD patients receiving MHD were enrolled. During MHD, all patients received rhEPO treatment for three months, followed by roxadustat combined with rhEPO treatment for three months. At the time before rhEPO treatment (T1), three months after rhEPO treatment (T2) and three months after rhEPO combined with roxadustat treatment (T3), the anemia, iron metabolism, blood lipid and inflammatory response indexes were detected. During the treatment, the adverse reactions were observed. Results showed that, compared with T1 and T2, at T3 the red blood cells, hemoglobin and hematocrit levels were significantly increased, the serum ferritin level, transferrin saturation and transferrin level were significantly increased, the hepcidin level was significantly decreased, the total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased, and the C-reactive protein and interleukin 6 levels were significantly decreased (all p < 0.05). There was no significant difference in the incidence of adverse reactions between two treatment periods (T1-T2 vs T2-T3; p > 0.05). In conclusion, compared with rhEPO, roxadustat combined with rhEPO can further improve the anemia status and iron metabolism, and reduce the blood lipid metabolism disorder and inflammatory response during MHD in CKD patients.