The differences in cost and efficacy between dapagliflozin and empagliflozin in combination with standard of care (SoC) raise the question of which regimen would be cost-effective in treating heart failure with reduced ejection fraction (HFrEF). This study evaluates the cost-effectiveness of dapagliflozin plus SoC (dapagliflozin-SoC) versus empagliflozin plus SoC (empagliflozin-SoC) or SoC alone for treatment of HFrEF. We developed a Markov model to estimate the cost-effectiveness of dapagliflozin-SoC, empagliflozin-SoC, and SoC alone from the healthcare system perspective over a lifetime horizon. Data on efficacy of dapagliflozin-SoC, empagliflozin-SoC, and SoC were obtained from randomized controlled trials. Costs were measured in 2022 US dollars, and effectiveness was measured in quality-adjusted life years (QALYs). Among three strategies, dapagliflozin-SoC was the most cost-effective strategy and dominated empagliflozin-SoC in an extended sense. Compared with SoC alone, dapagliflozin-SoC and empagliflozin-SoC had incremental cost-effectiveness ratios (ICER) of $56,782 and $89,258 per QALY, respectively. Dapagliflozin-SoC cost more $5524 but yielded more 0.20 QALYs than empagliflozin-SoC, with the ICER of $27,861 per QALY. The cost-effectiveness of dapagliflozin-SoC, empagliflozin-SoC, and SoC alone did not depend on diabetic status. However, empagliflozin-SoC was no longer cost-effective versus SoC alone in HFrEF patients without CKD, and dapagliflozin-SoC was not cost-effective versus empagliflozin-SoC in HFrEF patients with CKD. Dapagliflozin-SoC was cost-effective versus empagliflozin-SoC or SoC alone for treatment of HFrEF. •Dapagliflozin is more effective but costs more than empagliflozin for treating HFrEF.•Evidence on the cost-effectiveness of dapagliflozin versus empagliflozin is limited.•Dapagliflozin was cost-effective versus empagliflozin or standard of care for HFrEF.•Cost-effectiveness results varied by CKD status of HFrEF patients.