Objective <p>To investigate the treatment effect of the histone demethylase inhibitor GSK-J4, a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3 (JMJD3), in the treatment of periodontitis.</p> Methods <p>Gingival tissues from patients with moderate to severe chronic periodontitis and healthy controls were collected to evaluate JMJD3 expression via real-time quantitative reverse transcription PCR (RT-qPCR) and immunohistochemistry (IHC). Next, Sprague–Dawley (SD) rats were used to investigate the effect of GSK-J4 in vivo. The experimental periodontitis model was induced by upper first molar ligation and gingival sulcus injection of <i>Porphyromonas gingivalis.</i> The rats were divided into a healthy group, a periodontitis group, periodontitis plus GSK-J4 treatment groups (P + GSK-J4&#xa0;15 mg/kg or 25&#xa0;mg/kg), and a periodontitis plus dimethyl sulfoxide (DMSO) group (P + DMSO). After 4&#xa0;weeks, maxillary molar segments were assessed via micro-computed tomography (CT) and hematoxylin and eosin (HE) staining. Serum tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay (ELISA).</p> Results <p>Higher expression of the <i>Jmjd3</i> gene and JMJD3 protein was detected in human inflamed gingiva than in healthy gingiva (<i>P</i> &lt; 0.05). GSK-J4 administration reversed alveolar bone absorption [i.e., reduced alveolar bone crest (ABC)-cementoenamel junction (CEJ) distance], reduced inflammatory cell accumulation at the crest of the alveolar bone, and alleviated serum TNF-α levels in rats with periodontitis. Moreover, the number of H3K27me3-positive nuclei was greater in model rats treated with GSK J4 than in model rats.</p> Conclusions <p>The histone demethylase inhibitor GSK-J4 attenuated periodontal bone loss and inflammation in a rat periodontitis model by targeting JMJD3.</p>