Prolyl hydroxylase (PHD) inhibitors are suggested as therapeutic agents for tissue regeneration based on their ability to induce pro-angiogenic responses. In this study, we examined the effect of the PHD inhibitor dimethyloxalylglycine (DMOG) on odontoblast maturation and sought to determine the underlying mechanism using MDPC-23 odontoblast-like cells. DMOG significantly enhanced matrix mineralization, confirmed by alizarin red staining and by measurement of the calcium content. DMOG dose-dependently increased alkaline phosphatase activity and the expressions of dentin sialophosphoprotein (Dspp) and osteocalcin. To determine the underlying events leading to DMOG-induced Dspp expression, we analyzed the effect of DMOG on Runx2. Knockdown of Runx2 using siRNAs decreased Dspp expression and prevented DMOG-induced Dspp expression. DMOG enhanced the transcriptional activity and level of Runx2 protein but not Runx2 transcript, and this enhancement was linked to the inhibitory effects of DMOG on the degradation of Runx2 protein. The vascular endothelial growth factor (VEGF) siRNAs profoundly decreased the Runx2 protein levels and inhibited the DMOG-increased Runx2 protein. Recombinant VEGF protein treatment significantly and dose-dependently increased the transcriptional activity and level of the Runx2 protein but not Runx2 transcript. Dspp expression was also enhanced by VEGF. Last, we examined the involvement of the Erk mitogen-activated protein kinase and Pin1 pathway in VEGF-enhanced Runx2 because this pathway can regulate the stability and activity of the Runx2 protein. VEGF stimulated Erk activation, and the inhibitors of Erk and Pin1 hampered VEGF-enhanced Runx2 protein. Taken together, the results of this study provide evidence that DMOG can enhance Dspp expression through VEGF-induced stabilization of Runx2 protein, and thus, suggest that DMOG can be used as a therapeutic tool for enhancing odontoblast maturation in dental procedures.