This study aimed to evaluate the synergistic effect and safety of enarodustat combined with oral iron supplementation in the treatment of iron-deficient non-dialysis-dependent chronic kidney disease (NDD-CKD) patients with anemia. This single-center retrospective cohort study enrolled 120 iron-deficient NDD-CKD patients with anemia who had not received erythropoiesis-stimulating agents or intravenous iron within the preceding month. According to the treatment protocols administered, the participants were divided into a combination therapy group (n = 64) and a monotherapy group (n = 56). The combination therapy group (n = 64) received enarodustat combined with ferrous succinate sustained-release tablets, while the monotherapy group (n = 56) received ferrous succinate sustained-release tablets alone. Patients were followed for 8 weeks to evaluate hemoglobin (Hb) levels, iron metabolism parameters, erythropoietic parameters, and adverse events. After 8 weeks of treatment, Hb levels in the combination therapy group were significantly higher than those in the monotherapy group (P < .05). The achievement rate of Hb ≥ 100 g/L was 82.81% in the combination group versus 57.14% in the monotherapy group (P < .01); the achievement rate of Hb ≥ 110 g/L was 62.50% and 44.64%, respectively (P < .05). Serum ferritin, transferrin saturation, and serum iron in the combination therapy group were all significantly higher than those in the monotherapy group (all P < .001). The increase in reticulocyte count and hematocrit was more pronounced in the combination group (P < .001), while red blood cell count showed a numerical increase without reaching statistical significance. There was no significant difference in the overall incidence of adverse events between the 2 groups (P > .05), and no serious adverse events occurred in either group. This study indicates that enarodustat combined with oral iron supplementation may have a certain synergistic effect on iron-deficient NDD-CKD anemia compared with oral iron alone, potentially helping to improve hematological indicators and promote erythropoiesis, with an acceptable safety profile. This combined regimen may provide a preliminary reference for the management of NDD-CKD anemia.