ObjectiveTo evaluate the effect of rhein on eliminating the inflammation and promoting bone regeneration of periodontitis after local administration.Materials and MethodsIn vivo, periodontitis model was established in murine mandibular first molar by using ligature for 7 days, followed by ligature removal and local administration of rhein/vehicle for 7 consecutive days. In vitro, periodontal ligament fibroblasts were treated by LPS, along with the applications of rhein/vehicle. Histology and molecular biology approaches were applied for analysis.ResultsIn vivo, rhein alleviated periodontitis inflammation through downregulating the inflammatory index and promoted the osteogenic potential of PDL fibroblasts in a dosage‐dependent manner. The result of micro‐CT validated this phenomenon. In vitro, rhein administration inhibited the phosphorylation and nuclear translocation of P65, along with the arose runx2 level of PDL fibroblasts with the stimulus of LPS in mimicking periodontitis.ConclusionRhein played its inhibitory role on inflammation via curbing the activation of P65 but uprising the activities of Runx2 in PDL fibroblasts in periodontitis microenvironment. These data suggested that rhein could be an effective and potential clinical choice for the treatment of periodontitis.