Type 2 diabetes (T2D) is associated with impaired cutaneous wound healing, and can result in ulceration, infection and/or amputation. More than 26 million people in the U.S. have T2D and are vulnerable to epithelial‐related complications. New therapies regulating altered diabetic pathways are needed. Topical application of the opioid receptor antagonist naltrexone (NTX) dissolved in cream reverses delayed wound closure, and enhances angiogenesis and remodeling of full‐thickness wounds in T1D rats. NTX acts though the OGF‐OGFr axis to accelerate DNA synthesis and cell proliferation, and is a potential therapy for nonhealing wounds. In this study, the genetically obese mouse model db/db and normal C57Bl/6 mice received 6 mm diameter circular wounds on their dorsum. Wounds were treated topically 3 times daily with 10‐5 M NTX, or sterile saline, dissolved in cream, and photographed every 2 days. Db/db mice receiving saline had wounds that were 11‐92% larger than those in normal mice. NTX therapy reduced residual wound size by 13‐30% between days 8 and 14 compared to diabetic, vehicle‐treated wounds. Reepithelialization and DNA synthesis, as analyzed by epithelial thickness and BrdU labeling index, were accelerated in NTX treated wounds. These data indicate that a novel opioid receptor pathway is impaired under diabetic conditions, and modulation with NTX can regulate deleterious changes in healing seen in T2D.Grant Funding Source: American Diabetes Association