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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 6 months 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. [ABSTRACT FROM AUTHOR]