Introduction <p>In the advanced stages of chronic kidney disease (CKD), anemia impacts 78.9% to 96.5% of patients. Darbepoetin is utilized for the treatment of anemia associated with chronic kidney disease (CKD). The function of darbepoetin alfa can be clarified by comparing it with other agents. A comprehensive review and network meta-analysis were conducted to assess the safety and efficacy of Darbepoetin alfa compared to other agents in the treatment of anemia associated with chronic kidney disease (CKD).</p> Methods <p>A systematic review and network meta-analysis were conducted adhering to PRISMA-NMA guidelines. A systematic search was performed in databases Medline, Embase, and Scopus from inception to November 24, 2024, without language limitations. Randomized controlled trials assessing erythropoietin-stimulating agents (ESAs) or placebo in adults with chronic kidney disease (CKD)-related anemia were included. Data extraction and risk of bias assessment (RoB 2.0) were performed separately. Bayesian network meta-analysis using random-effects models was carried out using BUGSnet in R. Treatment effects were measured as odds ratios (ORs) or mean differences (MDs) with 95% credible intervals. Heterogeneity, inconsistency, and publication bias were evaluated, and certainty of evidence was assessed using the GRADE approach.</p> Results <p>In this network meta-analysis of 21 randomized trials involving over 4,000 CKD patients with anemia, Methoxy polyethylene glycol-epoetin beta showed the greatest hemoglobin increase, while Molidustat demonstrated the best cardiovascular and thrombotic safety despite lower efficacy. Daprodustat provided moderate hemoglobin improvement with a safety profile comparable to darbepoetin, showing no significant differences in mortality or cardiovascular events. Transferrin saturation, hypertension, and diabetes-related adverse events did not differ significantly across treatments. Roxadustat was associated with a higher incidence of gastrointestinal adverse events, particularly diarrhea.</p> Conclusion <p>Daprodustat and roxadustat indicated equivalent or higher efficacy when compared to darbepoetin in elevating hemoglobin levels in CKD-related anemia, with daprodustat demonstrating a good safety profile. While conventional ESAs remain beneficial, HIF-PHIs offer promising oral alternatives with possible benefits in cardiovascular safety and decreased hypertension risk. Further head-to-head trials are necessary to confirm these findings and guide individualized treatment strategies.</p> Clinical trial number <p>Not applicable.</p>