Objective <p>Periodontitis is a prevalent oral disease characterized by the destruction of tooth-supporting tissues. It exhibits a close association with leptin, a pleiotropic adipokine; however, the specific role and underlying mechanism of leptin in periodontitis remain largely elusive. In this study, a rat model of experimental periodontitis was established. Local injections of leptin and leptin antagonist were administered into the periodontal tissues of rats, respectively. By examining the histopathological and morphological changes of the periodontal tissues, as well as detecting the expression levels of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) in these tissues, we aimed to investigate the effects of local leptin levels on the progression of periodontitis.</p> Methods <p>A ligature-induced periodontitis model was established in Wistar rats. The rats were randomly divided into three groups: periodontitis + leptin (leptin group), periodontitis + saline (saline group), and periodontitis + leptin antagonist (antagonist group). Each group received local injections of leptin (0.4&#xa0;µg per rat per time), saline (10 µL per rat per time), or leptin antagonist (0.1&#xa0;µg per rat per time) in the periodontal tissue once every three days for a total of four weeks. Seventy-two hours after the last injection, the rats were sacrificed. Hematoxylin and eosin (HE) staining was used to observe histopathological changes in the periodontal tissues; micro-CT was used to examine alveolar bone parameters; and immunohistochemistry (IHC) and RT-PCR were performed to detect the expression of OPG and RANKL in the periodontal tissues of the rats.</p> Results <p>After 8 weeks of ligature, periodontitis was successfully induced. The rats in the leptin group presented significantly alleviated periodontitis symptoms. The extent of alveolar bone resorption in the leptin group was significantly lower than that in the saline and antagonist groups (<i>P</i> &lt; 0.05). OPG expression protein in the periodontal tissue of the leptin group was significantly greater than that in the saline and antagonist groups (<i>P</i> &lt; 0.05), whereas RANKL expression was significantly lower in the leptin group than in the saline and antagonist groups (<i>P</i> &lt; 0.05).</p> Conclusion <p>Local periodontal injection of leptin reduces the level of periodontal inflammation in rats with experimental periodontitis, mitigates alveolar bone resorption, increases OPG expression, and decreases RANKL expression. This study suggests that local periodontal injection of leptin may exert a protective effect against periodontal tissue destruction.</p>