Purpose <p>Diabetic keratopathy, a common ocular complication of diabetes, is characterized predominantly by corneal epithelial damage and peripheral nerve injury. This study examined the role of adiponectin (ADPN) in regulating the repair of the diabetic corneal epithelium and accompanying nerve injuries.</p> Methods <p>RNA sequencing was performed on total RNA isolated from corneal epithelium of streptozotocin (STZ)-induced type 1 diabetic mice and type 2 diabetic BKS.Cg-Dock7m +/+ Leprdb/Nju (db/db) mice to identify differentially regulated pathways and interactions. ADPN receptor expression was assessed. Recombinant ADPN, ADPN receptor 1/2 siRNA, and a phosphorylated AKT (p-AKT) inhibitor were then utilized in diabetic mice and in human corneal epithelial cells (HCECs) cultured under high-glucose conditions to evaluate corneal wound healing responses.</p> Results <p>ADPN receptor expression and p-AKT levels were downregulated in corneas of diabetic mice and in HCECs exposed to high glucose. Treatment with recombinant ADPN accelerated repair of corneal epithelial and nerve damage in both type 1 and type 2 diabetic mice, enhanced HCEC proliferation and migration under high-glucose conditions and activated AKT signaling. ADPN treatment also reduced neutrophil infiltration and inflammatory factor expression during wound repair. These beneficial effects were abolished by ADPN receptor 1 knockdown or AKT inhibition.</p> Conclusions <p>Our results demonstrate that ADPN promotes the corneal epithelium and nerve regeneration in diabetic mice via activation of the AdipoR1/AKT signaling axis and suppression of inflammatory responses. These findings identify ADPN as a promising therapeutic candidate for promoting corneal epithelial wound healing in diabetic conditions.</p>