Renal tubules are vulnerable targets of various factors causing kidney injury in diabetic kidney disease (DKD), and the degree of tubular lesions is closely related to renal function. Abnormal renal tubular epithelial cells (RTECs) differentiation and depletion of cell junction proteins are important in DKD pathogenesis. Caudal-type homeobox transcription factor 2 (CDX2), represents a key nuclear transcription factor that maintains normal proliferation and differentiation of the intestinal epithelium. The present study aimed to evaluate the effects of CDX2 on RTECs differentiation and cell junction proteins in DKD. The results demonstrated that CDX2 was mainly localized in renal tubules, and downregulated in various DKD models. CDX2 upregulated E-cadherin and suppressed partial epithelial-mesenchymal transition (EMT), which can alleviate hyperglycemia-associated RTECs injury. Cystic fibrosis transmembrane conductance regulator (CFTR) was regulated by CDX2 in NRK-52E cells, and CFTR interfered with β-catenin activation by binding to Dvl2, which is an essential component of Wnt/β-catenin signaling. CFTR knockdown abolished the suppressive effects of CDX2 on Wnt/β-catenin signaling, thereby upregulating cell junction proteins and inhibiting partial EMT in RTECs. In summary, CDX2 can improve renal tubular lesions during DKD by increasing CFTR amounts to suppress the Wnt/β-catenin signaling pathway.