Background: Chronic kidney disease (CKD) refers to permanent damage to the kidneys that occurs gradually over time. Further progression may be preventable depending on its stage. Purpose: This study was developed to evaluate the effect of a health literacy education program (HLEP) on mental health and renal functioning in patients with CKD. Methods: A single-blind, randomized controlled trial study was conducted. Data were collected from March 25 to December 18, 2021. Participants were randomly assigned to either the experimental group (n = 42), which received multidisciplinary care and HLEP, or the control group (n = 42), which received multidisciplinary care only. Data were collected at baseline (T1), Month 3 (T2), and Month 6 (T3), and the data included patient characteristics, estimated glomerular filtration rate, and responses to the Mandarin Multidimensional Health Literacy Questionnaire and Beck Depression Inventory. Results: After 6months of the HLEP intervention, the results of generalized estimating equations analysis showed that, compared with the control group, the experimental group had significantly higher health literacy at Month 3 (β = -3.37, 95% CI -5.68, -1.06), significantly improved depression at Month 3 (β = -2.24, 95% CI -4.11, -0.37) and Month 6 (β = -4.36, 95%CI -6.60, -2.12), and a significantly higher estimated glomerular filtration rate at Month 6 (β = 5.87, 95% CI 1.35, 10.38). Conclusions/Implications for Practice: The findings of this study may provide a reference for healthcare providers to educate patients with Stage 3-4 CKD using the HLEP. Positive effects on health literacy, depression, and renal function in patients with Stage 3-4 CKD were observed in the short term. Findings from this study may facilitate the implementation of multidisciplinary and nurse-led strategies in primary care to reinforce patients' health literacy, self-care ability, and adjustment to CKD as well as delay disease progression.