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Backgroud: Periodontitis is the leading cause of adult tooth loss, and those who smoke are at an increased risk of developing periodontitis. α7 nicotinic acetylcholine receptor (α7 nAChR) is proposed to mediate the potential synergistic effect of nicotine and inflammation in smoking-related periodontitis. However, this has not been experimentally demonstrated. Methods: We isolated and cultured human periodontal ligament stem cells (PDLSCs) from healthy and inflamed tissues. PDLSCs were treated with either inflammatory factors and/or nicotine. We measured expression of genes that are associated with osteogenic differentiation and osteoclast formation using RT-qPCR and western blot analyses. Besides, Immunohistochemical staining, micro-CT analysis, shRNA lentivirus infection, and tartaric acid phosphatase staining were used to measure α7 nAChR expression and function. Findings: Inflammation up-regulated α7 nAChR expression in both periodontal ligament tissues and PDLSCs. The up-regulated α7 nAChR contributed to the synergistic effect of nicotine and inflammation, leading to a decreased capability of osteogenic differentiation and increased capability of osteoclast formation-induction of PDLSCs. Moreover, the inflammation-induced up-regulation of α7 nAChR expression was partially dependent on the level of phosphorylated GSK-3β. Interpretation: This study provides experimental evidence for the pathological development of smoking-related periodontitis, and sheds new light on developing inflammation and α7 nAChR targeted therapeutics to treat and prevent the disease. Funding Statement: This study was supported by the National Natural Science Foundation of China (Grant No. 81670988, 81800924, 81601620 and 81800979) and the in-hospital scientific research program (Grant No. 2018LQ04) of Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi Province, China. Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Ethical approval was obtained from the ethics committee of the School of Stomatology, Air Force Military Medical University (Committee’s reference number: IRB-REV-2016093). All participants and guardians of the patients were informed on the objectives of this study. Written consents were obtained from all participants prior to conducting the study.