Abstract: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, driven by hyperglycemia-induced oxidative stress, ER stress, and mitochondrial apoptosis. This study examined the protective effects of Morin against hyperglycemia-induced renal tubular injury, alone or in combination with the SGLT2 inhibitor Empagliflozin, with emphasis on the ATF6-DAPK1 axis. HK2 cells were exposed to high glucose with or without Morin and/or Empagliflozin. Cellular stress, mitochondrial function, and apoptosis were assessed. Morin-DAPK1 binding was examined via molecular docking, surface plasmon resonance (SPR), and cell thermal shift assay (CETSA). db/db mice received vehicle, Empagliflozin, Morin, or their combination for 14 weeks, followed by renal histological, biochemical, and metabolic evaluations. Morin reduced ROS accumulation, ER stress (p-PERK, p-eIF2α, CHOP, cleaved ATF6), mitochondrial dysfunction, and apoptosis in HK2 cells. It suppressed DAPK1 mRNA expression via ATF6 inhibition and directly bound DAPK1 (Kd = 1.61 μmol·L⁻¹), disrupting its interaction with pro-apoptotic BAK/BIK. Empagliflozin indirectly downregulated DAPK1 through ER stress relief. Combination therapy synergistically reduced oxidative stress, preserved mitochondrial membrane potential, and prevented apoptosis. In db/db mice, both compounds improved renal structure, lowered blood glucose, reduced UACR, and inhibited kidney stress markers, with greater improvements in the combination group, which also alleviated hepatic steatosis. Morin exhibits renoprotective effects against high glucose-induced cellular stress and diabetic kidney disease, at least partially via DAPK1 targeting. Co-administration with Empagliflozin enhances these effects, supporting its potential as an adjunct therapy for hyperglycemia-induced kidney injury.