Vascularization is important in wound healing and essential for tissue ingrowth into porous tissue-engineering matrices. Furthermore, peri-implant tissue vascularization is known to be important for the functionality of subcutaneously implanted biosensors (e.g., glucose sensors). As a first exploration of the use of deoxyribonucleic acid (DNA)-based coatings for the optimization of biosensor functionality, this study focused on the effect of DNA-based coatings functionalized with vascular endothelial growth factor (VEGF) on in vitro endothelial cell behavior and vascularization of the peri-implant tissue in vivo. To that end, DNA-based coatings consisting of poly-D-lysine and DNA were functionalized with different amounts of VEGF (25 and 250 ng) and compared to non-coated controls and non-functionalized DNA-based coatings. The results demonstrated the superiority of VEGF-functionalized DNA-based coatings in increasing endothelial cell proliferation and migration in vitro over non-coated controls and non-functionalized DNA-based coatings. In vivo, a significant increase in vascularization of the peri-implant area was observed for VEGF-functionalized DNA-based coatings. Because no dosage-dependent effects were observed, future experiments should focus on optimizing VEGF concentration for this purpose. Additionally, the administration of VEGF in combination with other (pro-angiogenic) factors should be considered.