Abstract: In a healthy state, the interaction between the oral microorganisms, mucosal immune cells and epithelial barrier can maintain the oral microecological stability. However, the oral microecology is disrupted under a diseased state and various pathogenic bacteria and their virulence factors and metabolites irritate the immune system, which causes direct or indirect damage to the epithelial barrier, promotes the pathogenesis and progression of oral mucosal diseases, and triggers immune inflammatory response or the irreversible transformation from inflammation into cancer. We herein reviewed the interaction between oral microorganisms, immune cells and epithelial barrier from two perspectives, the maintenance of the oral homeostasis and the pathogenesis of oral mucosal diseases. We intended to gain further understanding of the oral mucosal homeostasis and the mechanism of action of the pathogenesis and progression of oral mucosal diseases, and to provide thereby ideas and scientific and theoretical basis for developing new strategies for the diagnosis and treatment of oral mucosal diseases through re-establishing mucosal homeostasis.