In clinical treatment, there is increasingly prevalent that traditional Chinese medicine treats common bone diseases including osteoporosis. Hydroxy safflor yellow A (HSYA), one of the essential compounds of Safflower, has strong effects to scavenge oxidative stress and inhibit apoptosis. It has been used as the therapy for thrombus, myocardial ischemia, and inflammation, but its effect on osteoporosis has not been explored. In this study, we found HSYA could enhance the cell viability and promote osteogenesis of hBMSC in vitro. Mechanistically, HSYA could increase the expression of β-catenin leading to its accumulation in the nucleus and activation of down-stream targets to promote osteogenesis. In addition, RNAseq and quantitative RT-PCR showed KDM7A was significantly increased by HSYA.The occupancy of H3K27me2 on β-catenin promoter was significantly decreased by HSYA, which could be reversed by silencing endogenous KDM7A. More importantly, HSYA could promote bone development in chick embryos and prevent ovariectomy(OVX)-induced bone loss in SD rats. Taken together, our study has shown convincing evidence that HSYA can promote osteogenesis and bone development via epigenetically regulating β-catenin and prevents ovariectomy-induced bone loss. HSYA might be used to treat some skeletal diseases such as osteoporosis.