While bone has the capability to heal itself, there is a great difficulty in reconstituting large bone defects created by heavy trauma or the resection of malignant tumors. Also, osteonecrosis of the femoral head (ONFH), which is caused by obstruction of the blood supply to bone cells and occurs in the young, is not amenable for successful bone regeneration. We developed VEGF- and BMP2-transfected adipose stem cells (ASCs) using electroporation that can effectively treat bone defects by providing rapid angiogenesis and osteogenesis. The optimal ratio of BMP2- to VEGF-transfected ASCs to enhance both osteogenesis and angiogenesis was 9 : 1. BMP2-/VEGF-transfected ASCs administered in this ratio effectively healed critical-size calvarial defects and long-bone segmental defects in immunosuppressed rats. The implanted cells did not migrate out of the implantation site by the 56th day. TAZ, TEAD, and ANKRD1 were overexpressed in BMP2-/VEGF-transfected ASCs, possibly proposing the mechanism of enhanced bone regeneration and angiogenesis. Our results suggest the possibility of using gene–cell therapy that can induce rapid angiogenesis and osteogenesis in inhospitable avascular environments including large bone defects and ONFH.