Background: Metabolic acidosis is a common complication in patients with chronic kidney disease (CKD) that accelerates disease progression and worsens overall health outcomes. Objective: This study compares the safety and effectiveness of sodium citrate and sodium bicarbonate in treating metabolic acidosis in CKD patients to determine the optimal therapeutic approach. Method: A prospective randomized clinical trial was conducted at the Department of Anesthesiology and ICU, Shaheed Monsur Ali Medical College and Hospital, Dhaka, Bangladesh, from October 2023 to September 2024. A total of 132 CKD patients with metabolic acidosis were randomly assigned to two groups: Group A (66 patients) received sodium citrate, and Group B (66 patients) received sodium bicarbonate. Safety, efficacy, and acid-base balance were monitored over 12 months. Results: Both sodium citrate and sodium bicarbonate significantly improved serum bicarbonate levels and reduced blood acidity. In Group A, 85% of patients showed a 50% reduction in acidemia, compared to 78% in Group B. However, Group A demonstrated superior gastrointestinal tolerance (10% side effects) compared to Group B (25% side effects). Sodium citrate also improved bone health markers, with a 15% improvement in calcium levels, while sodium bicarbonate patients had a 10% increase. However, sodium bicarbonate was more cost-effective. Conclusions: Sodium citrate appears to be more effective and better tolerated than sodium bicarbonate in treating metabolic acidosis in CKD patients, though cost considerations may influence therapeutic choices.