Periodontitis is one of the most prevalent inflammatory diseases, characterized by gingival inflammation and alveolar bone loss. MicroRNAs (MiRNAs) are important regulators of inflammation and involved in periodontitis pathogenesis. In this work, we studied the roles of microRNA-21 (miR-21) in periodontitis. MiR-21 is up-regulated in both periodontitis patients and the mice that induced with periodontitis. We tested the roles of miR-21 in the macrophages challenged by periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS). MiR-21 expression is up-regulated in P. gingivalis LPS-stimulated macrophages. MiR-21 mimic inhibits the pro-inflammatory cytokine production by macrophages, while miR-21 deficiency elevates the production of pro-inflammatory cytokines. Moreover, absence of miR-21 promotes activation of nuclear factor-κB (NF-κB) in P. gingivalis LPS- stimulated cells. In a murine periodontitis model, ligation induced exacerbated gingival inflammation and alveolar bone loss in miR-21 deficient mice than their wild-type littermates. These results demonstrated the anti-inflammatory function of miR-21 in vitro and in vivo, indicating miR-21 could be an interventional target for the control of periodontitis. Copyright © 2018 Elsevier Ltd. All rights reserved.