Abstract: Trained immunity is a state of enhanced immune responsiveness based on innate immune (epigenetic) memory. It has recently been reported that trained immunity plays an important role in the comorbidity of periodontitis and rheumatoid arthritis (RA). Epigenetic modifications in hematopoietic stem and progenitor cells (HSPCs) can activate trained immunity in bone marrow-derived cells, a mechanism closely associated with the onset and progression of periodontitis and other related systemic diseases. Exhibiting hyper-reactivity, trained immune cells are capable of migrating to distant joint sites and eliciting a more intense inflammatory response upon external stimulation. This review focuses on the underlying mechanisms of trained immunity and its involvement in both periodontitis and RA. Understanding the role of trained immunity in the association between periodontitis and RA provides valuable insights for further research and the development of therapeutic strategies for inflammatory comorbidities, such as periodontitis and RA.