We evaluated the effects of zoledronic acid (ZOL) on human gingival fibroblasts (HGFs) and human umbilical vein endothelial cells (HUVECs) associated with wound healing in oral soft tissues. HGFs and HUVECs were divided into two groups: a culture media control group and a group exposed to ZOL (50 μM). Cell proliferation was measured after 2, 4, 6, and 8 days. The migration ability of cells was measured for each experiment using the wound healing assay. The apoptosis rate was confirmed using the apoptosis assay. Culture supernatants were collected from each experimental group and vascular endothelial growth factor (VEGF) production in the culture media was measured using enzyme-linked immunosorbent assay (ELISA). Further, the expression level of VEGF-A was evaluated and compared using real-time quantitative polymerase chain reaction. The proliferation and migration abilities of both HGFs and HUVECs were confirmed to be suppressed by the addition of ZOL, resulting in apoptosis. ELISA revealed that the quantity of VEGF produced in HGFs was significantly higher in the ZOL group than in the control group until 2 days after the addition of ZOL. In HGFs, the mRNA expression levels of intracellular VEGF-A increased with the addition of ZOL, demonstrating the production of VEGF. In contrast, in HUVECs, although the mRNA expression levels of endogenous VEGF-A increased with the addition of ZOL, VEGF production was considerably decreased in the culture supernatant, indicating the possibility of abnormalities in the autocrine functions of endogenous VEGF or intracellular signal transduction of exogenous VEGF. These data suggest the utility of therapeutic approaches directed toward abnormalities in VEGF intracellular signaling to improve medication-related osteonecrosis of the jaw soft-tissue healing.