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. Glehnia littoralis has been used to relieve inflammation in traditional Chinese medicine, and the effect of bergapten, a compound isolated from G. littoralis, 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 Porphyromonas gingivalis-lipopolysaccharides (PG-LPS). The effects of bergapten were further confirmed in PG-LPS– and ligature-induced in vivo periodontitis 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. In vivo studies confirmed that bergapten reduced inflammatory infiltration and cytokine expression while restoring periodontal tissue loss. This study identifies a novel activity of bergapten and highlights its potential as a therapeutic agent for periodontitis with fewer treatment-related side effects.