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OBJECTIVE To determine the anti-osteoclastogenic potential of ginsenoside Rb3 for the treatment of periodontitis. METHODS Anti-osteoclastogenic effect was determined using RANKL-induced RAW264.7 cells and murine bone marrow-derived macrophages followed by TRAP and phalloidin staining. Expression of osteoclastogenesis-related genes and proteins were examined by qPCR and WB. Activation of signaling pathways were detected by WB and IHC techniques. Experimental periodontitis rat model was built up by gingival injections of P. gingivalis LPS. After 21 days of Rb3 treatment, rats were sacrificed for micro-CT, IHC, H&E and TRAP staining analyses. RESULTS Rb3 dramatically inhibits RANKL-induced osteoclastogenesis. Nfatc1, Mmp9, Ctsk, Acp5 mRNA and MMP9, CTSK proteins were dose-dependently downregulated by Rb3 pretreatment. WB results revealed that Rb3 suppressed activations of p38 MAPK, ERK and p65 NF-κB, and the inhibition of ERK was most pronounced. Consistently, IHC analysis revealed that p-ERK was highly expressed in alveolar bone surface, blood vessels, odontoblasts and gingival epithelia, which were notably suppressed by Rb3 treatment. H&E staining and micro-CT analyses showed that Rb3 significantly attenuated gingivitis and alveolar bone resorption in rats. CONCLUSION Rb3 inhibits RANKL-induced osteoclastogenesis, and attenuates P. gingivalis LPS induced gingivitis and alveolar bone resorption in rats via ERK/NF-κB signaling pathway.