Periodontal diseases are infections of the structures that surround and support the teeth; they are characterized by local inflammation and alveolar bone loss. Most treatments focus on only one aspect, inhibiting inflammation, or promoting osteoblasts. We set out to develop a new method that would intervene in the two aspects simultaneously. Adiponectin (APN), secreted by adipocytes, inhibits the inflammatory response and promotes osteogenesis. However, its role in human periodontal ligament cells (hPDLCs) is unclear. Therefore, we aim to investigate whether APN could suppress lipopolysaccharide (LPS)-induced inflammation and promote osteogenesis in hPDLCs. In the present study, we stimulated hPDLCs with LPS in the presence or absence of APN. Real-time PCR and Western blotting results demonstrated that APN partially inhibited the activation of the classical nuclear factor κ-B (NF-κB) pathway. These results were confirmed by a change of expressions of NF-κB downstream inflammatory genes, such as decreased cyclooxygenase (COX)-2 and tumor necrosis factor α (TNF-α), along with increased interleukin (IL)-10. As for the role of APN in osteogenesis, Alizarin Red S staining showed that APN treatment induced more calcium deposition nodules than controls. We also found that APN enhanced the expression of osteoblast-related genes (osteopontin (OPN), collagen 1, osteocalcin, alkaline phosphatase, runt-related transcription factor 2 (RUNX2), and bone morphogenetic protein 2) in hPDLCs via the APPL1 (the adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1)/p38 signal transduction pathway. Therefore, APN inhibits LPS-induced inflammation and promotes osteogenesis in hPDLCs and may have potential therapeutic value in treating periodontitis by inhibiting the inflammatory lesions and contributing to bone tissue regeneration.