Bone fractures are a major cause of morbidity and mortality, particularly in patients with diabetes, who have a high incidence of fractures and exhibit poor fracture healing. The NO/cGMP/protein kinase G (PKG) signaling pathway mediates osteoblast response to estrogens and mechanical stimulation, and is downregulated in diabetes by a defective enzyme, soluble guanylate cyclase (sGC). Here, we used a mouse mono-cortical defect model to stimulate bone regeneration in diabetic and non-diabetic mice which were treated with either vehicle or a NO-independent activator of oxidized sGC, cinaciguat. Diabetic mice demonstrated low Vegfa and Bmp2/4 expression in bone and impaired bone regeneration after injury;​ notably, the cGMP-elevating agent cinaciguat restored Vegfa and Bmp2/4 expression, full bone healing, but had no effect on mechanical properties of uninjured bone in the diabetic animals, likely due to the short treatment duration. We conclude that PKG1 is a key orchestrator of VEGF and BMP signaling during bone regeneration and propose pharmacological PKG activation as a novel therapeutic approach to enhance fracture healing