Background: Heart failure (HF) is a major public health concern with high morbidity and mortality rates worldwide. Beta-blockers are cornerstone therapies for heart failure, particularly in patients with reduced ejection fraction (HFrEF). This study aims to compare the efficacy of three commonly prescribed beta-blockers—carvedilol, metoprolol, and bisoprolol—on clinical outcomes in HF patients. Objective: To evaluate the comparative efficacy of carvedilol, metoprolol, and bisoprolol in improving left ventricular ejection fraction (LVEF), reducing hospitalizations, and enhancing survival in heart failure patients. Methods: A multicenter randomized controlled trial was conducted involving 1,200 heart failure patients with HFrEF. Participants were randomly assigned to one of three groups to receive either carvedilol, metoprolol, or bisoprolol for 12 months. Primary outcomes included LVEF improvement, reduction in heart failure-related hospitalizations, and overall mortality. Secondary outcomes assessed adverse events and quality of life (QoL). Results: Carvedilol demonstrated the most significant improvement in LVEF, compared to metoprolol and bisoprolol. Patients on carvedilol had a 30% reduction in hospitalization rates and a 25% improvement in survival compared to the other two groups. Metoprolol and bisoprolol showed similar benefits, with slightly less efficacy in reducing hospitalizations and improving LVEF. Safety profiles were similar across all three groups, with carvedilol showing a higher incidence of bradycardia and hypotension during dose escalation. Conclusion: Carvedilol provides superior benefits in improving LVEF, reducing hospitalizations, and enhancing survival in patients with heart failure compared to metoprolol and bisoprolol. While all three beta-blockers are effective, carvedilol should be considered as the preferred first-line therapy in heart failure with reduced ejection fraction.