Objectives: Diabetes and hypertension are the most common causes of chronic kidney disease. Calcium channel blockers are beneficial in blood pressure reduction while also stall kidney degeneration. The aim of this study was to compare the cost-effectiveness of manidipine to amlodipine as an add-on to renin-angiotensin system blockers (RASBs) to slow down kidney degeneration in hypertensive patients with diabetes mellitus and proteinuria. Methods: A lifetime Markov decision model was used to evaluate total costs and quality-adjusted life-years (QALYs) from published data on clinical outcomes and Thai data on cost and humanistic outcomes. This study adopted a societal perspective. Results: The results demonstrated that the total cost of the treatment with manidipine was 69,892.28 baht compared to 458,508.22 baht for amlodipine, and the QALYs were 9.15 and 6.84 years, respectively. Conclusions: Manidipine was more cost effective than amlodipine in the treatment of Thai hypertensive patients with diabetes mellitus and proteinuria, and it was associated with better clinical outcomes in terms of QALYs and lower costs than amlodipine. Manidipine should be used as the first choice as an add-on to RASBs. The results of this study could contribute to appropriate decision making by policymakers.