Objective: Type 2 diabetes (T2D) is associated with impaired cutaneous wound healing and can result in ulceration, infection, and/or amputation. More than 25 million people in the United States have T2D and are vulnerable to epithelial-related complications. Current therapies are limited in their efficacy. New treatments for full-thickness cutaneous wounds that focus on underlying diabetic pathways are needed. Approach: Topical application of the opioid receptor antagonist naltrexone (NTX) dissolved in cream reverses delayed wound closure in type 1 diabetic rat by the acceleration of reepithelialization and enhancement of angiogenesis and remodeling. NTX blocks the opioid growth factor (OGF)-OGF receptor (OGFr) axis and upregulates DNA synthesis and cell proliferation. To investigate whether NTX is an effective therapy for T2D wound closure, genetically obese mice (db/db) and normal C57Bl/6J mice received full-thickness cutaneous wounds. Wounds (5 mm in diameter) were treated topically three times daily with 10-5 M NTX or sterile saline dissolved in cream and photographed every 2 days. Results: Wounds in db/db mice treated with saline were 11-92% larger than those in normal mice throughout the 2-week observation. Topical NTX therapy in T2D mice reduced the residual wound size by 13-30% between days 8 and 14 relative to diabetic mice receiving saline. Reepithelialization and DNA synthesis, as analyzed by epithelial thickness and BrdU labeling indexes, respectively, were accelerated in NTX-treated wounds. Innovation and Conclusion: These data suggest that the OGF-OGFr axis plays a role in epithelial-related complications of T2D and that blockade of this pathway by NTX may be an effective treatment for wound repair.