Purpose <p>Puerarin (Pue) has recently been reported to have therapeutic effects on periodontitis (PD). However, there is insufficient evidence, and the mechanism involved has not yet been revealed. This work delved to explore the exact therapeutic effects and molecular mechanism of Pue in treating PD.</p> Methods <p>PD mouse (C57BL/6&#xa0;N mouse) model constructed by <i>Porphyromonas gingivalis</i>-lipopolysaccharide (Pg-LPS) induction was treated with Pue. Therapeutic efficacy of Pue for PD was examined by a series of experiments. PD cell model was induced by treating human periodontal ligament cells with Pg-LPS. Therapeutic effects of Pue on PD cell model, along with the potential molecular mechanism, were explored by logical experiments. Rescue experiments based on in vitro and in vivo studies were implemented to validate the molecular mechanism of Pue in treating PD.</p> Results <p>In PD mice, Pue treatment relieved inflammation and bone destruction, facilitated osteogenic differentiation and autophagy in periapical tissues. In PD cell model, Pue treatment facilitated osteogenic differentiation and mitochondrial autophagy; suppressed inflammation and mitochondrial reactive oxygen species; maintained mitochondrial membrane potential and mitochondrial kinetic homeostasis; and activated mitochondrial Mitofusin 2 (Mfn2). However, these influences of Pue on PD cell model were eliminated by CsA (mitochondrial autophagy inhibitor). The enhanced mitochondrial autophagy induced by Pue was reversed by Mfn2 silencing. Through in vivo data, Mfn2 knockdown counteracted the therapeutic effects of Pue on PD mice.</p> Conclusion <p>Pue exerted therapeutic effects on PD, possibly by enhancing mitochondrial autophagy via activating mitochondrial Mfn2. This might be a cure for PD.</p> Graphical Abstract <p></p>