The aim of the systematic review was to analyze the use of mesenchymal stem cells (MSC) and biomaterial for periodontal regeneration from preclinical animal models and human. Electronic databases were searched and additional hand-search in leading journals was performed. The research strategy was achieved according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The including criteria were as follows: MSC, biomaterial, in vivo studies, with histologic and radiologic analysis and written in English. The risk of bias was assessed for individual studies. A total of 50 articles were selected and investigated in the systematic review. These results indicate that MSC and scaffold provide beneficial effects on periodontal regeneration, with no adverse effects of such interventions. Future studies need to identify the suitable association of MSC and biomaterial and to characterize the type of new cementum and the organization of the periodontal ligament fiber regeneration.