Background: Studies have found the pivotal role of miRNAs in the progression of postmenopausal osteoporosis (OP). However, the function of miRNAs in OP is unclear. This study aimed to explore the biological functions of microRNA-151a-3p in OP. Methods: RT-qPCR was employed to assess the expression of microRNA-151a-3p in serum isolated from OP patients and healthy controls. Dual-energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) of the lumbar spine. The expression levels of c-Fos, NFATc1, and TRAP were tested by Western blot. Ovariectomized (OVX) rats were treated with antago microRNA-151a-3p or antago NC, and then serum and lumbar vertebrae were collected for ELISA and bone histomorphology analysis. Results: The expression of microRNA-151a-3p in postmenopausal women with osteoporosis was significantly up-regulated, and microRNA-151a-3p level was negatively correlated with BMD. During osteoclastogenesis, microRNA-151a-3p level was obviously increased. Overexpression of microRNA-151a-3p promoted the differentiation of RANKL-induced THP-1 and RAW264.7 cells into osteoclasts, whereas silencing of microRNA-151a-3p resulted in the opposite results. Silencing of microRNA-151a-3p in OVX rats altered osteoclastogenesis-related factors and raised BMD. Conclusion:MicroRNA-151a-3p could partly regulate osteoporosis by promoting osteoclast differentiation, and miRNA-151a-3p could be a potential therapeutic target for postmenopausal osteoporosis.