This systematic review aimed to: (a) generate a descriptive synthesis of preclinical studies assessing the therapeutic potential of regulatory T lymphocytes (Tregs) to arrest periodontitis, (b) evaluate the methodological heterogeneity of the reviewed animal studies and (c) assess the risk of bias (RoB) of the included studies. The electronic search for animal studies included the MEDLINE, EMBASE, Web of Science and LILACS databases. In addition, a manual search assessed the highâranked scientific journals in âperiodontics/immunologyâ and the references listed in the included studies. There were no language, year or publication status restrictions. Two independent reviewers selected and extracted the data, and Cohen's Kappa coefficient was calculated to determine the interâexaminer agreement. The Systematic Review Center for Laboratory Animal Experimentation's (SYRCLE) tool was used to assess the RoB. A total of 21 of the 425 studies obtained from the database search were included. Treg function was mainly described in Porphyromonas gingivalisâinduced periodontitis (57.1%) in mice (76.2%), where Treg suppression was strongly related to disease progression and Treg induction was strongly related to immunoâinflammatory response reduction. Of those 21 studies, eight included eight animal experiments using three distinct therapeutic approaches, including: P. gingivalisâdriven immunization (n = 3), retinoic acid inoculation (n = 2) and antiâinflammatory molecules in polymeric carriers (n = 3), which could modulate the Treg activity through cytokine production (interleukinâ10 and transforming growth factorâÎČ1), CCâchemokineâ and CCâchemokine receptorâmediated chemoattraction (CCL22 and CCR4) or Th17âassociated receptor activator of nuclear factor ÎșB ligand (RANKL) downregulation. However, the studies with animal experiments did not specify the randomization sequences and housing conditions that were used, and therefore, 42.11% of the entries were rated as unclear RoB. Distinct therapeutic strategies involving Tregs could potentially suppress the immunoâinflammatory response and restore alveolar bone homeostasis during periodontitis. Nevertheless, important methodological variability, poor reporting of treatment effect estimates and unclear RoB suggest using caution when assessing the results of these studies.