Osteoporosis is a systemic disease with complex etiology and high incidence, resulting in a huge economic burden. For a long time, the search of new therapeutic pharmaceuticals has never stopped. Bone loss is related to the imbalance between bone resorption via osteoclast and bone formation via osteoblast. In recent years, the role of immunity and inflammation in the development of osteoporosis has attracted wide attention. Different cytokines, chemokines and endocrine factors regulate osteoclastogenesis by activating different macrophage subtypes, including pro-inflammatory M1 and anti-inflammatory M2. Bilobalide (Bil), an active Ginkgo biloba ingredient, has aroused our great interest because of its antioxidant and anti-inflammatory activities. In this study, we confirmed that Bil attenuated osteoclasts generation induced by receptor activator of nuclear factor- kappa B ligand (RANKL) through upregulating sirtuin 3 (SIRT3) and negatively regulating NF-κB signaling. Furthermore, Bil promotes M2 polarization of macrophages in a dose-dependent manner. In vivo studies provided evidence that Bil is able to improve bone density in ovariectomized (OVX) mice models. Based on the above results, we have the reason to believe that Bil has potential therapeutic value in osteoclast-mediated osteoporosis and may have the potential as a therapeutic drug in the future.