Osteoporosis (OP), a systemic and chronic bone disease, is distinguished by low bone mass and destruction of bone microarchitecture. Ginsenoside Compound-K (CK), one of the metabolites of ginsenoside Rb1, has anti-aging, anti-inflammatory, anti-cancer, and hypolipidemic activities. We have demonstrated CK could promote osteogenesis and fracture healing in our previous study. However, the contribution of CK to osteoporosis has not been examined. In the present study, we investigated the effect of CK on osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. The results showed that CK inhibited receptor activator for nuclear factor-κB ligand (RANKL)-mediated osteoclast differentiation and reactive oxygen species (ROS) activity by inhibiting the phosphorylation of NF-κB p65 and oxidative stress in RAW264.7 cells. In addition, we also demonstrated that CK could inhibit bone resorption using bone marrow-derived macrophages. Furthermore, we demonstrated that CK attenuated bone loss by suppressing the activity of osteoclast and alleviating oxidative stress in vivo. Taken together, these results showed CK could inhibit osteoclastogenesis and prevent OVX-induced bone loss by inhibiting NF-κB signaling pathway.© 2023. The Author(s).