Picroside II (Pic II) has been used to treat many skeletal diseases. Postmenopausal osteoporosis (PMOP) is a serious skeletal disease that significantly threatens the health of postmenopausal women. We aimed to explore the roles and mechanisms of Pic II in PMOP. PMOP models were established by performing bilateral ovariectomy in rats and stimulating osteoblasts with HO. In vivo, micro-CT imaging, HE and MASSON staining were performed, and E, Ca/Cre, ALP, BGP, SOD, MDA, Fe and ROS levels were determined. In vitro, cell viability, apoptosis, mineralization, GSH and Fe levels were measured. Both animal and cell experiments detected the expressions of YY1, TGFβ1, SLC7A11, GPX4, RunX2 and BMP2 proteins. Moreover, PMOP cells were treated with N-Acetyl-L-cysteine (a ferroptosis inhibitor) to further explore the mechanisms of Pic II on PMOP. Pic II attenuated bone loss, improved femur pathological injury and increased collagen volume fraction for PMOP rats Furthermore, after Pic II treatment, PMOP rats exhibited decreased Ca/Cre, ALP, MDA, Fe and ROS levels, but increased E, BGP and SOD levels. In vitro, Pic II intervention elevated cell viability, GSH level and mineralization, suppressed apoptosis, and reduced ROS and Fe levels. Moreover, both animal and cell experiments observed that Pic II upregulated YY1, GPX4, SLC7A11, Runx2 and BMP2 expressions, but downregulated TGFβ1 expression. Importantly, Pic II exhibited similar effects to N-Acetyl-L-cysteine in PMOP cells. Pic II may regulate YY1/TGFβ1 axis by inhibiting osteoblast ferroptosis to alleviate PMOP, suggesting that Pic II may be a novel agent for PMOP treatment.