Dental diseases seriously affect the quality of life. Studying the mechanism of dental pulp stem cells (DPSCs) had far-reaching significance for the therapy of dental diseases. In this paper, we studied the small ubiquitin-like modifier-specific protease 1 (SENP1) and hypoxia-inducible factor (HIF)-1α functions in angiogenesis under anoxic conditions. Flow cytometry was used to identify and sort DPSCs. Reverse transcription-quantitative polymerase chain reaction and Western blot were carried out to analyze the expression of von Willebrand factor, vascular endothelial growth factor receptor 2, vascular endothelial cadherin, and CD31. Besides, si-SENP1 and si-HIF-1- levels were changed by cell transfection. Tube formation ability was carried out by tubulogenesis assay. Furthermore, the levels of HIF-1α and SENP1 were also tested by Western blot. We obtained DPSCs and induced them to differentiate into vessels and form tubules in vitro. On the basis of this, we demonstrated hypoxia enhanced HIF-1α and SENP1 expression. si-HIF-1α downregulated SENP1 expression and angiogenesis ability under hypoxia, and si-SENP1 downregulated HIF-1α expression and angiogenesis ability under hypoxia. Under hypoxia, SENP1 and HIF-1α formed a positive feedback loop and played a momentous part in angiogenesis.