Periodontitis is a typical osteoimmune disorder characterized by inflammatory absorption of alveolar bone, and is the main cause for loose and fall off teeth in adults. Bacterial antigens stimulate the osteoclasts and aggravate periodontal inflammation, so it is of great significance for treatment of periodontitis to control inflammation and block the resorption of alveolar bone. Milk fat globule epidermal growth factor 8 (MFG-E8), as a lipophilic glycoprotein on the cell membrane, is expressed in multiple organs and histiocytes and participates in the bone immune response. MFG-E8 is involved in the development of osteoinflammatory diseases including periodontitis, so can be used as a new marker for the diagnosis of periodontal disease, and also has the potential of targeted therapy for periodontitis with the aggravation of osteoinflammatory diseases, the decreased expression of MFG-E8, reduction of osteoclasts formation and inhibition of alveolar bone resorption. MFG-E8 may be committed to early diagnosis and intervention to control the disease in order to reduce the economic burden of patients and improve the quality of life, and may become a hot spot for the treatment of periodontitis and other osteoinflammatory diseases in the future. Therefore, the research progress of MFG-E8-mediated osteoimmunology in periodontitis has reviewed in present paper to provide new ideas for clinical diagnosis and treatment of periodontitis.