Background and objective Anemia is a common prognosis of chronic kidney disease (CKD). It is predominantly managed with synthetic erythropoietin. The principal objective of this study was to compare the cost-effectiveness of the use of short-acting erythropoietin with the long-acting one to maintain serum hemoglobin (Hb) concentration within the range of 10.5-12 g/dL. Method This was a retrospective cohort study involving patients diagnosed with stage 5 CKD according to the Saudi Society of Nephrology and Transplantation conducted at eight tertiary care centers in the Tabuk region, Saudi Arabia. We compared the cost-effectiveness of long-acting erythropoietin with the short-acting one. The decision analysis model and Markov model were established to simulate a cohort of 55-year-old patients to estimate the incremental cost and quality-adjusted life-year (QALY) for chronic hemodialysis patients (CHP) treated with either darbepoetin-alfa or epoetin-beta for at least nine months. The incremental cost per QALY was the main outcome marker for using both medications. Serum HB levels were monitored on a monthly basis and costs were calculated. Results A total of 291 CHP met our inclusion criteria; 194 of them were treated with darbepoetin-alfa while 97 were treated with epoetin-beta. The mean age was 56.3 ± 11.2 years for the darbepoetin-alfa group and 55.2 ± 7.8 years for the epoetin-beta cohort. The baseline serum Hb was 10.68 ± 0.98 g/dL for darbepoetin-alfa patients and 11.63 ± 0.32 g/dL for the epoetin-beta group (p=0.003). We observed a significant difference between the percentage of patients successfully treated with epoetin-beta and those managed with darbepoetin-alfa (80.4% vs. 63.92%, p=0.01) with considerably less cardiovascular side effects. The average annual cost per patient was estimated at $919.47 and $12,319.41 for epoetin-beta and darbepoetin-alfa respectively. Also, the average effectiveness was 0.58 for darbepoetin-alfa vs. 0.61 for epoetin-beta. The average cost-effectiveness ratio was $980.25 and $15,023.66 with an incremental cost difference of -$966 in favor of epoetin-beta compared to darbepoetin-alfa. Conclusion Based on our findings, treating anemia in hemodialysis patients using epoetin-beta is very cost-effective compared to managing them with darbepoetin-alfa.