Objective To systematically evaluate the application of stem cells in tissue engineering for regeneration of periodontal defects and to provide a basis for clinical application. Methods PubMed, The Cochrane Library, EMbase, SinoMed, CNKI and Wanfang database were searched for randomized controlled trial (RCT) studies on periodontal defect regeneration using bone marrow mesenchymal stem cells, adipose tissuederived stem cells, periodontal ligament stem cells (PDLSCs), dental pulp stem cells (DPSCs), gingival mesenchymal stem cells, stem cells from apical papilla and other odontogenic stem cells. Chinese and English literature as of May 9, 2021 (without limitation on retrieve starting date) were searched, and included RCT studies were followed for at least 3 months. Two reviewers independently screened the literature, extracted basic research information, the situation of the research object and outcome measures including probing depth (PD), clinical attachment level (CAL), bone defect depth (BDD) and gingival recession (GR). Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0) was used to evaluate bias risk in included studies and Meta-analysis was performed using RevMan 5.4 software. Results A total of 182 teeth were included in 7 RCT studies. The experimental group was treated with stem cell tissue engineering technology (87 cases), and the control group was treated with conventional periodontal regeneration therapy without stem cell (95 cases). In the meta-analysis, a significant difference between experimental and control groups was found for PD [mean difference (MD) = -0.66, 95% CI (-1.11, -0.22), P= .004], CAL [MD = -1.11, 95% CI (-1.45, -0.77), P < .00001], BDD [MD = -0.99, 95% Cl (-1.42, -0.57), P < .00001] and GR [MD = -0.35, 95% Cl (0.62, -0.07), P= .01]. By observing the 4 outcome indicators of periodontal tissue regeneration, the improvement of CAL was the best, while the improvement of GR was poor. In the subgroup analysis of follow-up time, PD improved best at 6 months compared with other follow-up times [MD= -1.07, 95% CI (-1.58, -0.55), P < .0001]. However, in the subgroup analysis of CAL, BDD and GR, there was no statistical significance among follow-up time. Conclusions Compared with conventional periodontal regeneration therapy, the application of stem cells in tissue engineering exhibits a significant advantage in promoting periodontal defect regeneration and allows for complete periodontal regeneration possibly. Due to limitations related to the number and quality of the included studies, additional large-sample and high-quality clinical studies are needed to support future meta-analyses.