Astragaloside IV (AS-IV) is a natural plant extract that enhances osteoblast activity, and therefore, has the potential to treat osteoclast‑related diseases. Such diseases include osteoporosis, periodontal disease, rheumatoid arthritis and aseptic prosthesis loosening. However, data associating the effects of AS‑IV on osteoclasts are limited. The aim of the present study was to assess the effect of AS‑IV on osteoclasts in vitro and in vivo. The in vitro studies demonstrated that AS‑IV exerts potent inhibitory effects on the ligand of the receptor activator of nuclear factor‑κB‑induced osteoclastogenesis and revealed the mechanism of action of AS‑IV, which inhibited osteoclastogenesis by suppression of the extracellular signal‑regulated kinase signaling pathway. The in vivo studies proved that AS‑IV attenuated titanium particle‑induced osteolysis in a mouse calvarial model. Collectively, the findings of the study suggest that AS‑IV is a potential natural agent for the treatment of osteoclast-related diseases.