Osteoclasts have an additional demand for cholesterol compared to normal cells. Liver X receptors (LXRs) are famous for regulation of lipid and cholesterol metabolism. Therefore, we propose that the LXR β agonist can regulate the cholesterol balance in osteoclasts to inhibit osteoclast differentiation. Here, we designed and synthesized a novel LXRβ agonist by introduction of the privileged fragments from anti-osteoporosis agents to the spiro[pyrrolidine-3,3'-oxindole] scaffold which is a novel scaffold of LXR agonists in our previous research. As a result, seven LXRβ agonists inhibited osteoclastogenesis with IC50 values ranging from 0.078 to 0.36 μM. Especially, the most potent LXRβ agonist B9 significantly inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro and in vivo. Furthermore, B9 selectively activated LXRβ to promote intracellular cholesterol exclusion in osteoclasts and reduce extracellular cholesterol uptake and thereby inhibited osteoclast production. This study provides a new strategy to develop LXRβ agonists for osteoporosis.