Herbal Sambucus williamsii HANCE (SWH) is a folk medicine with a long history of safe use for treatment of bone fractures and joint diseases in China. The present study was designed to investigate if SWH extract could be used for treatment of postmenopausal osteoporosis. SWH extracts (30 or 60 mg/100 g body weight/d) were orally administrated to four-months-old ovariectomized (OVX) rats for 3 months. SWH extracts did not alter weight gain and uterus weight in OVX rats. SWH extracts significantly increased serum Ca levels (p<0.05, vs. OVX control group) as well as decreased urinary Ca excretion (p<0.01, vs. OVX control group) in OVX rats. The upregulation of serum alkaline phosphatase, serum osteocalcin as well as urinary deoxypyridinoline levels by OVX was suppressed by treatment with SWH extracts in rats (p<0.05, vs. OVX control group). SWH extract increased the stiffness of femur at both dosage (p<0.05, vs. OVX control group) and increased tibial bone mineral density at 60 mg/100 g body weight/d (p<0.05, vs. OVX control group) in OVX rats. Our results indicate that orally administrated SWH extracts can decrease urinary calcium excretion and bone turnover rate in OVX rats, resulting in positive effects on biomechanical strength of bone and bone mineral density. This study is the first to report that SWH could be considered as a potential candidate for management of postmenopausal osteoporosis. Then in vitro experiments were performed to determine the potential molecular mechanism of the anti-osteoporotic effect of SWH. Results suggested that chloroform fraction and ethyl acetate fraction of SWH can inhibit osteoclastogenesis osteoclast by modulating the expression of osteoprotegrin (OPG) and receptor activator of NF-kappaB ligand (RANKL) mRNA in osteoblastic UMR 106 cells. Both of them increased OPG mRNA and decreased RANKL mRNA expression, resulting in a dose-dependent increase in OPG/RANKL mRNA ratio (p<0.01, vs. vehicle-treated). Taken together, SWH treatment can effectively suppress the OVX-induced increase in bone turnover and its effects might be mediated by a decrease in osteoclastogenesis.