The present study was conducted to determine whether metformin, a low-cost drug widely prescribed to control type 2 diabetes mellitus, stimulates production of angiogenic factors to potentially enhance vascularization of dental pulp stem cell (DPSC)-based craniofacial tissue engineered bone. Bone tissue engineering utilizing stem cells, growth factors and scaffolds offer an attractive alternative for regenerating large craniofacial osseous defects versus autologous bone grafts. Yet, successful stem cell-based bone regeneration highly depends on proper adaptation of cells to hypoxia and reestablishment of a functional microvasculature. Recent reports show that metformin induces DPSC’s osteogenic differentiation; however, it remains unknown whether metformin stimulates DPSC-derived, pro-angiogenic responses to support bone regeneration. We found that metformin induced a marked but variable increase in DPSC-derived angiogenic factors, including VEGF and angiogenin, which were further amplified by hypoxia. These results point to a novel, pro-angiogenic action of metformin to potentially enhance DPSC-based vascularized craniofacial skeletal regeneration.