ObjectivesCystathionine‐γ‐lyase (CTH) has been proved to involve in inflammation and bone remolding, implying its potential role in the progression of periodontitis. This study was aimed to investigate the function of CTH and its relation to the macrophage polarization in periodontitis.Materials and methodsBone marrow‐derived macrophages (BMDMs) from wild‐type (WT) and Cth knockout (Cth−/−) mice were stimulated with lipopolysaccharide (LPS) in vitro and pro‐inflammatory cytokines were analyzed by qRT‐PCR. Ligature‐induced periodontitis was established on WT and Cth−/− mice. Histological analysis, tartrate‐resistant acid phosphatase staining, immunostaining, and Western blot were performed to analyze the periodontium destruction and M1 macrophage polarization.ResultsCth expression in BMDMs was upregulated upon increasing LPS stimulation. Deletion of Cth suppressed BMDMs inflammatory response with decreased Il1b, Il6, and Tnf mRNA. Cth−/− mice with periodontitis showed attenuated bone loss and impaired osteoclast differentiation compared with WT. Moreover, Cth knockout hindered M1 macrophage polarization, reduced the expression of IL‐1β, IL‐6, and TNF‐α in periodontally diseased tissue.ConclusionThis study demonstrated that CTH played an important role in regulating the inflammatory responses and periodontitis tissue destruction. Importantly, Cth knockout suppressed M1 macrophages polarization in periodontitis.