Objective <p>This study investigated the effect of cannabinoid receptor 2 (CB2R) on macrophage polarization and inflammatory severity in periodontitis, elucidating CB2R’s potential role in the disease.</p> Methods <p>Chronic periodontitis was induced by ligating maxillary second molars with orthodontic filaments in wild-type (WT) and CB2R knockout (CB2R^-/-) mice. Unligated mice served as controls. After 3 weeks, maxillae were harvested. Micro-CT evaluated modeling success and quantified alveolar bone resorption. HE staining assessed periodontal tissue destruction. Immunohistochemistry (IHC) analyzed macrophage polarization, while RT-qPCR measured mRNA levels of macrophage markers and inflammatory cytokines.</p> Results <p>1. Micro-CT revealed significantly greater alveolar bone resorption in both CB2R^-/- and WT periodontitis groups versus controls (<i>P</i> &lt; 0.05), with CB2R^-/- mice exhibiting more severe resorption than WT mice.2. HE staining demonstrated increased bone loss, inflammatory infiltration, and tissue destruction in periodontitis groups, most pronounced in CB2R^-/- mice.3.IHC indicated elevated M1/M2 macrophage markers in periodontitis groups. M1 marker iNOS expression was significantly higher in CB2R^-/- versus WT mice (<i>P</i> &lt; 0.05), while M2 marker Arg-1 showed no intergroup difference (<i>P</i> &lt; 0.05)0.4.RT-qPCR confirmed upregulated macrophage markers and inflammatory cytokines in periodontitis groups, with significantly higher expression in CB2R^-/- mice (<i>P</i> &lt; 0.05). CB2R^-/- mice also exhibited elevated M1/M2 and IL-6/IL-10 ratios versus WT mice (<i>P</i> &lt; 0.05).</p> Conclusions <p>CB2R deficiency exacerbates alveolar bone resorption and inflammatory severity in periodontitis, potentially by dysregulating macrophage M1/M2 polarization and inflammatory cytokine expression.</p>