In the oral maxillofacial region, there are significant demands for repairing severe tissue defects caused by congenital malformations, oncologic resection, post-traumatic loss, and pathologic degenerative destruction such as periodontitis. Mesenchymal stem cells (MSCs) are adult stem cells whose multipotency has been investigated for therapeutic applications. This review highlights the main MSCs involved in the tissue regeneration of oral maxillofacial region and recent advances in dental MSC-based tissue regeneration and treatments in this region. MSCs isolated from oral maxillofacial sources have higher proliferation rates and are more capable of forming bone and dental tissues. Large animal models of oral diseases or defects were established and treated with MSCs. Miniature pigs or dogs more closely mimic disease in humans and provide a useful means for translating research into clinical applications. MSCs exert other beneficial effects, including immunomodulation and paracrine processes. The immunoregulatory properties of MSCs facilitate their application to oral diseases and tissue regeneration. Besides autologous MSCs being an excellent cell source for tissue engineering and regenerative medicine, allogeneic MSC-based treatment also provides a safe and effective therapeutic modality, the use of allogeneic MSCs in highly standardized clinical trials could lead to a better understanding of their real-life applications, which sheds light on potential clinical applications for treating oral diseases.