Background and Purpose Recent evidence suggests that postmenopausal osteoporosis is associated with increased bone resorption function in osteoclasts, of which Cathepsin K is a key molecule. In this study, we aimed to screen small molecule compounds targeting Cathepsin K and evaluate whether they affect osteoclast bone resorption function. Experimental Approach We screened out the small-molecule compound NVP-BHG712 targeting CTSK by molecular docking, and studied its pharmacological effect on bone resorption function of osteoclasts. To this end, we evaluated bone mass changes in postmenopausal mice by μCT, ELISA, and H&E staining. In addition, we also investigated the effects of NVP-BHG712 on osteoclast differentiation, bone resorption function and expression of osteoclast differentiation related factors in vitro. Key Results Surprisingly, we found that oral NVP-BHG712 treatment significantly reduced bone loss in postmenopausal mice. In vitro osteoclast culture, it was found that this effect was achieved by inhibiting osteoclast differentiation and bone resorption. Meanwhile, NVP-BHG712 significantly decreased the expression of genes related to osteoclast differentiation, including CTSK, MMP9, CTR, IP3R1, IP3R3, and OC-STAMP. Conclusion and Implications The present findings suggest that NVP-BHG712 reduces bone resorption function by inhibiting osteoclast differentiation, and is a potential drug for preventing and treating postmenopausal osteoporosis and other diseases.