Drug therapy is an effective and essential treatment method for periodontitis. However, the systemic use of traditional antibiotic drugs has the disadvantages of low bioavailability, short duration of action and the possibility of causing a series of complications, which limits their use in the clinic. In this study, we prepared nanomicelles of distearoylphosphatidyl-ethanolamine-N-poly (ethyleneglycol) 2000 (DSPE-PEG) loaded with rhein (Rh-NMs) for local administration to treat periodontitis. In vitro, Rh-NMs slowly released approximately 55% of the active ingredient over 24 h, reduced the secretion of inflammatory cytokines and reactive oxygen species (ROS) by lipopolysaccharide (LPS)-stimulated cells. In vivo, Rh-NMs significantly inhibited gingivitis and alveolar bone resorption and played a therapeutic role in local tissue for more than 24 h. Therefore, Rh-NMs have the potential to be a novel and promising therapeutic agent for periodontitis management.