Exosome secretion is an important paracrine way of endothelial progenitor cells (EPCs) to modulate resident endothelial cells. The osteocalcin (OCN)-expressing EPCs has been found to be increased in cardiovascular disease patients and considered to be involved in the process of coronary atherosclerosis. Since OCN has been proved to prevent endothelial dysfunction, this study aims to evaluate the effect of exosomes derived from OCN-overexpressed EPCs on endothelial cells. Exosomes derived from EPCs (Exos) and OCN-overexpressed EPCs (OCN-Exos) were isolated and incubated with rat aorta endothelial cells (RAOECs) with or without the inhibition of OCN receptor, G-protein coupled receptor family C group 6 member A (GPRC6A). The effects of exosomes on the proliferation activity of endothelial cells were evaluated by CCK-8 assay and the migration of endothelial cells were detected by wound healing assay. Tube formation assay was used to test the influence of exosomes on the angiogenesis performance of endothelial cells. Here we presented that OCN was packed into Exos and able to be transferred to the RAOECs via exosomes incorporation, which was increased in OCN-Exos groups. Compared with Exos, OCN-Exos had better efficiencies on promoting RAOEC proliferation, migration and tube formation. The promoting effects were impeded after the inhibition of GPRC6A expression in RAOECs. These data suggest that exosomes from OCN-overexpressed EPC have beneficial regulating effect on endothelial cells, which involved the enhanced OCN-GPRC6A signaling.