<p>Periodontitis is a periodontal disease that causes tooth loss in severe cases due to chronic inflammation. The role of ER stress in this process of periodontal inflammation has not been identified. <i>Glehnia littoralis</i> has been used to relieve inflammation in traditional Chinese medicine, and the effect of bergapten, a compound isolated from <i>G. littoralis</i>, on ER stress during the progression of periodontitis was evaluated. The efficacy of bergapten was evaluated in silico and in vitro using human periodontal ligament cells stimulated with <i>Porphyromonas gingivalis</i>-lipopolysaccharides (PG-LPS). The effects of bergapten were also demonstrated in two in vivo model on PG-LPS- and ligature-induced periodontitis animal models. In silico simulation revealed that bergapten bound to the active site and downregulated the gene expression levels of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1β, which are major inflammatory cytokines in periodontitis. Osteoblast differentiation was induced in human periodontal ligament cells stimulated with PG-LPS. These effects were confirmed to occur through the regulation of ER stress by bergapten. An in vivo study was conducted to support these in vitro results, and bergapten alleviated inflammatory infiltration and inflammatory cytokine expression levels, along with restoring periodontitis-induced periodontal tissue loss. This study reveals the novel physiological activity of bergapten and suggests its potential as a new periodontitis therapeutic agent that can reduce the side effects caused by various surgical treatments and therapies used to treat periodontitis.</p>