Bone resorptive cytokines contribute to bone loss in periodontal disease. However, the involvement of SIRT1 in high-mobility group box 1 (HMGB1)-induced osteoclastic cytokine production remains unknown. The aim of this study was to investigate the role of SIRT1 in the responses of human periodontal ligament cells to HMGB1 and to identify the underlying mechanisms. The effect of HMGB1 on osteoclastic cytokine expression and secretion, and the regulatory mechanisms involved were studied by ELISA, reverse transcription-polymerase chain reaction, and Western blot analysis. HMGB1 upregulated the mRNA expression levels of the osteoclastic cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-11, and IL-17. In addition, HMGB1 upregulated RANKL mRNA expression, and SIRT1 mRNA and protein expression. The upregulation of these cytokines by HMGB1 was attenuated by pretreatment with inhibitors of p38 mitogen-activated protein kinase and NF-κB, as well as neutralizing antibodies against Toll-like receptors 2 and 4. Inhibition of SIRT1 by sirtinol or SIRT1 siRNA blocked the HMGB1-stimulated expression of RANKL and cytokines. These results suggest that the inhibition of SIRT1 may attenuate HMGB1-mediated periodontal bone resorption through the modulation of osteoclastogenic cytokine levels in human periodontal ligament cells.