Periodontitis refers to the inflammation of gums and the surrounding structures and caused by a bacterial infection. The infection occurs owing to poor oral hygiene and could destroy the bone and the gum over time if left untreated. The present study identified the involvement of a key long noncoding RNA (lncRNA), i.e. FGD5-AS1, in the pathogenesis of periodontitis by assessing its expression in the gingival tissues of patients diagnosed with chronic periodontitis (CP). Overexpression of FGD5-AS1 in primary human periodontal ligament cells (PDLCs) significantly reduced the lipopolysaccharide (LPS)-induced periodontitis, whereas its suppression aggravated this injury. Moreover, the miR-142-3p was markedly expressed in the gingival samples of patients diagnosed with CP and LPS-induced PDLCs. We found that the FGD5-AS1-mediated reduction in the inflammation was mediated through downside regulation of miR-142-3p, as evident from the upregulation of SOCS6, a target gene of miR-142-3p. Furthermore, the association between FGD5-AS1 and NF-κB pathway was detected. FGD5-AS1 was found to protect against LPS-stimulated PDLC injury through restraining the NF-κB signals. Based on these findings, we conclude that up-regulation of lncRNA FGD5-AS1 could protect against periodontitis via regulating the miR-142-3p/SOCS6/NF-κB signals. Therefore, the FGD5-AS1/miR-142-3p/SOCS6 axis may act as an important indicator in explaining the pathogenesis of periodontitis.