INTRODUCTION: Chronic kidney disease (CKD) is a pervasive disease of the current century that usually affects the adult population, especially people with diabetes and hypertension. According to the recent studies, inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction are determining risk factors in the pathogenesis of CKD. Melatonin as a strong antioxidant is produced in various tissues including the kidneys. The present clinical trial aims to examine the efficacy of melatonin supplementation on metabolic parameters, oxidative stress, and inflammatory biomarkers in diabetic patients with CKD. METHODS: This is a double-blind, randomized, placebo-controlled clinical study that will be investigated the impacts of melatonin supplementation in diabetic patients with CKD. Laboratory findings will be applied to diagnose diabetic CKD. Forty-eight eligible diabetic subjects with CKD will be selected and randomly assigned to receive 5 mg melatonin tablets or identical placebo twice daily for 10 weeks. Participants will be asked to remain on their usual diet and physical activity. The primary outcome of this study is changes in oxidative stress and inflammatory biomarkers. The secondary outcomes include changes in lipid profile, renal function indicators, fasting blood sugar and serum insulin, systolic and diastolic blood pressure (SBP and DBP), serum phosphorous concentration, sleep quality, body weight, body mass index (BMI), and waist circumference (WC). Statistical analysis will be conducted using the SPSS software (version 25). DISCUSSION: We hypothesize that melatonin administration may be useful for treating diabetic CKD by modulating oxidative stress, inflammation, regulating lipid metabolism, and increasing insulin sensitivity through different mechanisms. The current trial will exhibit the effects of melatonin, whether negative or positive, on diabetic CKD status. ETHICAL ASPECTS: The current trial received approval from Medical Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.SHARIATI.REC.1402.072). TRIAL REGISTRATION: This study had been registered in Iranian Registry of Clinical Trials. REGISTRATION NUMBER: IRCT20170202032367N9 on 11 August 2023. https://www.irct.ir/trial/70709 .