Periodontal diseases often cause alveolar bone defects, and clinically, autologous bone graft or bone substitute implantation is mainly used for treatment. However, there are many defects in the existing treatment methods, such as shortage of donors, bone resorption, infection, and bleeding after transplantation. Oral tissue is one of the important sources of stem cells. Oral-derived stem cells can promote the regeneration of blood vessels and periodontal tissues, and has become a research hot-spot recent years in the treatment of periodontal diseases. However, there are many factors that affect the efficacy of stem cells in treatment of periodontal diseases and are not easy to control. In the past, researchers mainly focused on the therapeutic effects and mechanisms of stem cells themselves, and seldom studied the interaction between the recipient or donor microenvironment and stem cells, and how to establish the best therapeutic strategy. The microenvironmental regulation mechanism of periodontal tissue regeneration induced by stem cells has been summarized in present paper, and the influence of the microenvironment on the function, biological behavior and curative effect of stem cells have been expounded from the aspects of hormone levels, metabolic status and immune regulation, so to deepen researchers' understanding of microenvironmental regulation during stem cell therapy, and optimize and construct more effective periodontal disease treatment strategies.