Tissue defects resulting from craniomaxillofacial congenital developmental anomalies significantly compromise both the physical and psychological health of patients. Due to the constraints of autologous and allogeneic transplantation, stem cell-based regenerative therapies present a promising alternative. As a crucial source of cell therapy, mesenchymal stem cells (MSCs) are widely employed for tissue regeneration on account of their exceptional proliferative capacity and multidirectional differentiation potential. Nevertheless, several challenges remain in clinical application, such as the immunogenicity, long-term safety, and therapeutic efficacy. This review centers on the application of craniomaxillofacial MSCs in the treatment of craniomaxillofacial congenital defects and the challenges confronted in regenerative therapy, aiming to provide new perspectives for the clinical management of these conditions.