Osteoradionecrosis (ORN) of the jaw is a late and major complication of radiation therapy for head and neck cancers. The pathogenesis of ORN is yet to be fully clarified, which has put limitations on effective prevention and treatment of this condition. Radiation induced tissue hypoxia has been associated with development of ORN based on the previously proposed ‘hypoxia-hypocellularhypovascular’ theory of ORN pathophysiology. This indicates that radiation cycles during head and neck cancer therapy cause sustained hypoxia leading to death of bone cells. Therefore, we hypothesized that severe hypoxia tested at 0.1% oxygen tension alters plasticity of jaw mesenchymal stem cells, the essential osteoprogenitors vital for bone healing. We assessed the effect of severe hypoxia (0.1% oxygen) on responsiveness of human orofacial mesenchymal stem cells (hOFMSCs) isolated from the jaw based on post-hypoxic survival and in vitro/in vivo multilineage differentiation of surviving cells. The effects of hypoxia inducible factor-1 alpha (HIF-1α) and Endoplasmic reticulum stress response (ERSR) signaling pathways on activation of vascular endothelial growth factor (VEGF) by OFMSCs in response to severe hypoxia were also assessed. We found that OFMSCs succumbed to severe hypoxia because hypoxia depleted osteoprogenitor pools of OFMSCs. However residual surviving OFMSCs retained appreciable multilineage differentiation capacity. We also found that activation of both HIF-1α and ERSR signaling pathways in response to severe hypoxia coregulate downstream activation of VEGF to support recovery actions of residual OFMSCs from severe hypoxia. These results indicate that hypoxia plays a role in the pathogenesis of ORN and that resilience of OFMSCs to severe hypoxia can be further explored for tissue regeneration in irradiated jaw bone.