Periodontitis is a complex inflammatory disease affecting the supporting structures of teeth and is associated with systemic inflammatory disorders. Regulator of G-protein signaling 12 (RGS12), the largest protein in the RGS protein family, plays a crucial role in the development of inflammation and bone remodeling. However, the role and mechanism(s) by which RGS12 may regulate periodontitis have not been elucidated. Here, we showed that ablation of RGS12 in Mx1 hematopoietic cells blocked bone loss in the ligature-induced periodontitis model, as evidenced morphometrically and by micro-computed tomography analysis of the alveolar bone. Moreover, hematopoietic cell-specific deletion of RGS12 inhibited osteoclast formation and activity as well as the production of inflammatory cytokines such as IL1β, IL6, and TNFα in the diseased periodontal tissue. In the in vitro experiments, we found that the overexpression of RGS12 promoted the reprogramming of macrophages to the proinflammatory M1 type, but not the anti-inflammatory M2 type, and enhanced the ability of macrophages for migration. Conversely, knockdown of RGS12 in macrophages inhibited the production of inflammatory cytokines and migration of macrophages in response to lipopolysaccharide stimulation. Our results demonstrate for the first time that inhibition of RGS12 in macrophages is a promising therapeutic target for the treatment of periodontitis.