Osteoporosis, as a severe public health problem worldwide, causes systemic damage to bone mass, strength, and microstructure with an increased propensity for fragility fractures. Given the inherent adverse effects associated with long-term use of current prescription medications for osteoporosis treatment, identifying natural alternatives to existing treatment methods is imperative. Pteryxin (PTX), a natural coumarin, is isolated from the Peucedanum species belonging to the family Apiaceae. PTX has been reported to have antioxidant, anti-inflammatory and anti-obesity properties. However, its effect on osteoporosis has not been clarified. Our study confirmed that PTX could attenuate the formation of osteoclasts and bone resorption on a dose-dependent basis in vitro. Consistently, in vivo ovariectomy (OVX)-induced osteoporosis models simulating the physiological characteristics of postmenopausal women showed that PTX could partially reverse the bone loss caused by OVX. Further study of its mechanism revealed that PTX might block the MAPK and Ca²⁺-calcineurin-NFATc1 signaling pathways by decreasing the reactive oxygen species (ROS) level in osteoclasts to dampen the expression of critical transcriptional NFATc1 and downstream osteoclast-specific genes. Overall, PTX may present a new or alternative treatment option for osteoporosis.