Periodontitis, an inflammatory disease of oxidative stress, occurs due to excess reactive oxygen species (ROS) contributing to cell and tissue damage which in turn leads to alveolar bone resorption as well as the destruction of other periodontal support tissues. With significant recent advances in nanomaterials, we considered a unique type of nanomaterials possessing enzyme-like characteristics (called nanozymes) for potential future clinical applications, especially in light of the increasing number of studies evaluating nanozymes in the setting of inflammatory diseases. Here, we introduced a therapeutic approach for the management of periodontitis utilizing an injection of cerium oxide nanoparticles (CeO2 NPs) in situ. In this study, our synthesized CeO2 NPs could act as ROS scavengers in the inflammatory microenvironment with ideal outcomes. In vitro and in vivo experiments provide strong evidence on the roles of CeO2 NPs in scavenging multiple ROS and suppressing ROS-induced inflammation reactions stimulated by lipopolysaccharides. Moreover, CeO2 NPs could inhibit the MAPK-NFκB signalling pathway to suppress inflammatory factors. In addition, the results from a rat periodontitis model demonstrate that CeO2 NPs could exhibit a remarkable capacity to attenuate alveolar bone resorption, decrease the osteoclast activity and inflammation, and consequently improve the restoration of destroyed tissues. Collectively, our present study underscores the potential of CeO2 NPs for application in the treatment of periodontitis, and provides valuable insights into the application of nanozymes in inflammatory diseases.