Oral potential malignant disorders (OPMDs) are a group of oral mucosal lesions with a risk of cancer transformation. The microenvironment surrounding the epithelial tissue is closely related to the malignant transformation of OPMDs. However, the changes and role of the periepithelial microenvironment during the malignant progression of OPMDs are not yet fully understood. This review discuss the impact of changes in the periepithelial microenvironment on the malignant transformation of OPMDs from following aspects: the immune microenvironment, stromal microenvironment, metabolic microenvironment, and oral microorganism. In the immune microenvironment, the immune surveillance capacity of periepithelial immune cells weakens, and some of these cells interact with malignant cells, resulting in an immunosuppressive microenvironment. Cells in the matrix promote the malignant transformation of OPMDs through the secretion of cytokines and nutritional support, along with extracellular matrix degradation and local angiogenesis. Epithelial cells undergo metabolic reprogramming during malignant transformation, while the resulting hypoxic microenvironment can further promote the malignant transition of epithelial cells. Oral microorganism fosters the malignant transformation of OPMDs by inducing inflammatory responses and creating hypoxic conditions.