A population pharmacokinetic and pharmacodynamic model (PK/PD) of darbepoetin alfa following intravenous (IV) or subcutaneous (SC) administration in participants with chronic kidney disease (CKD) was developed. Darbepoetin alfa concentrations from 96 CKD participants, who received IV or SC darbepoetin alfa, and Hgb concentration from 332 CKD participants not on dialysis, who received SC doses of darbepoetin alfa, were used to develop the PK/PD model. An open 2-compartment model with sequential zero- and first-order absorption was used to characterize darbepoetin alfa pharmacokinetics. Darbepoetin alfa was assumed to trigger concentration-dependent stimulation of production of progenitor cells of red blood cells (RBCs) in bone marrow, which become red blood cells and died after life span expiration. Model evaluation was performed through nonparametric bootstrap and posterior predictive checks. Absolute bioavailability, total mean absorption time, clearance, and volume of distribution were estimated to be 44%, 52 h, 3.4 L/d/70 kg, and 5.9 L/70 kg, respectively. The estimates of drug potency, efficacy, and RBC life span were 0.41 ng/mL, 64%, and 77 days, respectively. Pharmacokinetic or pharmacodynamic parameters of darbepoetin alfa were not affected by age and sex. The qualified model supports the use of darbepoetin alfa administered biweekly (SC) in CKD patients for anemia correction and monthly (SC) for hemoglobin maintenance. In addition, the model is deemed appropriate to conduct simulations to support dose selection for additional clinical studies.