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Objective To explore the pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) and the mechanism of Traditional Chinese Medicine(TCM)-based prescription for "Bringing Blood Downward" targeting SONFH through the OPG/RANKL/RANK signaling pathway. Methods Fifty male SD rats were randomly divided into model group and control group. The rats in the model group were treated with LPS and methylprednisolone to build a SONFH model. After 6 weeks, two rats were randomly selected respectively from the two groups, and the SONFH model was confirmed by histomorphological examination under light microscopy. The rats in a low, medium and high dose treatment groups (group L, M, and H) were intragastrically administrated with the Prescription for "Bringing Blood Downward" at concentrations of 2.5/5/10 g/kg. While the rats in the model group and control group were intragastrically administrated with normal saline at a concentration of 5 g/(kg·d). The pathological changes and expression levels of OPG, TRAF-6, and RANKL in each group were examined 4 weeks later. Results Compared with the model group, chondrocytes and cell matrix of groups L, M and H were less reduced, osteoclastic absorption and trabecular structure were less destroyed and the cells were less adipose. The adipocyte density in the control group and each treatment group was significantly lower than that in the model group (P < 0.01). In the control group, the bone marrow cavity area was smaller than that in the model group(P < 0.05), but there was no significant difference between each dose treatment groups and the model group (P > 0.05). The expression levels of OPG, RANKL, TRAF-6 and OPG/RANKL ratio in the control group and groups L, M and H were significantly lower than those in the control group (P < 0.01). Conclusion The TCM-based prescription for "Bringing Blood Downward" works to treat SONFH byregulating the activity of osteoclasts and osteogenic differen- tiation process of osteoblasts, improving the microcirculation environment of the femoral head, and inducing the formation of trabecular bone through the OPG/RANKL/RANK signaling pathway. It functions with its multitargetsin diverse methods. [ABSTRACT FROM AUTHOR]