Chronic kidney disease (CKD) is a global health problem characterized by progressive renal fibrosis and excessive extracellular matrix deposition. Oxidative stress and epigenetic regulation, particularly through microRNAs (miRNAs), play crucial roles in the pathogenesis of CKD. In this study, we investigated the role of urinary miR-144-3p, which is upregulated in rats with CKD induced by diabetes and hypertension, in renal fibrosis progression, particularly its regulation of the nuclear factor erythroid-2-related factor 2 (NRF2) pathway. Our findings revealed elevated miR-144-3p levels and reduced NRF2 and target gene levels in kidney tissues of streptozotocin-treated spontaneously hypertensive rats. In vitro experiments demonstrated that miR-144-3p directly binds to the 3'-untranslated region of nrf2, suppressing the NRF2 pathway in renal tubular epithelial cells. Additionally, the profibrogenic factor transforming growth factor (TGF)-β1 increased miR-144-3p expression. TGF-β1-induced NRF2 suppression and reactive oxygen species elevation were found to be mediated through miR-144-3p upregulation. In vivo, cilostazol, an antiplatelet drug with an NRF2-activating effect, ameliorated renal injury in diabetic hypertensive rats by decreasing TGF-β1 and miR-144-3p levels while increasing NRF2 and its target gene levels in the kidneys. These findings highlight the potential therapeutic value of targeting the miR-144-3p/NRF2 pathway to attenuate CKD progression in hypertensive diabetic conditions.