Macrophages play pivotal roles in the immune response, acting as antigen-presenting cells that influence both inflammation and tissue homeostasis. This chapter explores the versatile functions of macrophages in periodontal disease, a chronic inflammatory condition characterized by the destruction of periodontal tissues. Macrophages are primarily derived from circulating monocytes and exhibit distinct polarization states, notably M1 and M2. In the context of periodontal disease, M1 macrophages are closely associated with pro-inflammatory responses and tissue destruction, while M2 macrophages facilitate tissue repair and resolution of inflammation. Evidence demonstrates that macrophage polarization is a dynamic continuum influenced by various environmental cues such as cytokines. Notably, an increase in M1 macrophages correlates with the active stages of periodontal disease, whereas M2 macrophages are more prevalent during the recovery phase. Furthermore, macrophages significantly contribute to bone metabolism by regulating osteoclastogenesis, with M1 macrophages promoting bone resorption through the secretion of inflammatory cytokines. This chapter also addresses the role of macrophages in the interaction between systemic diseases and periodontal disease and potential therapeutic strategies aimed at targeting macrophage polarization to mitigate inflammation and enhance periodontal regeneration. Overall, macrophages play various roles in the progression of periodontal disease and gingival homeostasis. Further understanding of the multifaceted roles of macrophages is essential for developing effective host modulation therapies that restore immune balance, improve treatment outcomes, and advance our comprehension of the complex mechanisms underlying oral health and disease. This knowledge holds promise for the development of innovative therapeutic approaches in the management of periodontal disease.