Vascular dysfunction and disruption of the balance between different subtypes of macrophages are key factors contributing to the poor healing of diabetic wounds. This study revealed that ginseng-derived nanoparticles (GDNPs) can promote angiogenesis and regulate macrophage polarization in the diabetic wound microenvironment, thereby promoting diabetic wound healing. GDNPs were found to significantly promote the cell viability of human umbilical vein endothelial cells (HUVECs) exposed to H(2)O(2) under high glucose (HG) conditions while increasing the angiogenic capacity of HUVECs, and attenuating the elevated levels of H(2)O(2)-induced oxidative stress. Moreover, GDNPs effectively regulated macrophage (RAW264.7) polarization towards the M2 phenotype, exerting anti-inflammatory effects. The results indicated that GDNPs act on the PI3K/AKT/HIF-1α and TLR4/MyD88/MAPK pathways to promote angiogenesis, reduce inflammatory and oxidative stress, modulate macrophage polarization, and accelerate wound healing in diabetes. This study provides insights into the therapeutic benefits of GDNPs in diabetic wound healing.