Abstract: Objective To evaluate the therapeutic effects of Bushen Yisui Formula (BSYS) on postmenopausal osteoporosis (PMOP) and to explore its epigenetic mechanism in anti-osteoporosis activity. Methods Forty 9-week-old SPF female C57BL/6J mice were randomly divided into a sham-operated (Sham) group, a model (OVX) group, an estrogen (E2) group, and a Bushen Yisui formula (BSYS) group. A mouse model of osteoporosis was established by bilateral ovariectomy, followed by 8 weeks of drug intervention. Bone microstructure was assessed by bone tissue staining and Micro-CT analysis. Serum bone metabolism markers were measured by ELISA. Western blot was used to detect osteogenic and osteoclastic proteins, as well as the expression of histone demethylase KDM7A and estrogen receptor α (ERα) in bone tissue. In vitro experiments were performed using MC3T3-E1 osteoblast cell line. Cells were treated with BSYS-containing serum, and the expression of KDM7A, ERα, and osteogenic differentiation-related proteins was examined. Results Compared with the OVX group, both the BSYS and E2 groups showed significant improvement in trabecular microstructure. Serum levels of bone formation markers BALP and OCN increased, whereas the bone resorption marker TRACP-5b decreased. Meanwhile, the levels of osteogenic proteins BMP2, OCN, and Collagen I were increased, while the osteoclastic protein Cathepsin K was reduced in the BSYS group. Compared with the E2 group, the levels of KDM7A and ERα proteins in bone tissue were increased in the BSYS group. In vitro experiments showed that BSYS-containing serum upregulated KDM7A and ERα expression and promoted the expression of osteogenic proteins including BMP2, OCN, and Collagen I, with a concentration-dependent effect on osteogenic differentiation. Conclusions BSYS exerts a bidirectional regulatory effect of promoting bone formation and inhibiting bone resorption. Its osteogenic mechanism may be associated with upregulating KDM7A expression and activating the ERα expression.