In the present study, the effects of total flavonoids of Rhizoma Drynariae (TFRD) and calcium carbonate (CaCO 3 ) on osteoporosis (OP) were assessed in a rat model of OP. For this purpose, 36 Sprague-Dawley rats, aged 3 months, were randomly divided into a group undergoing sham surgery (sham-operated group), model group (OP group), CaCO 3 group (OP + CaCO 3 group), TFRD group (OP + TFRD group), TFRD combined with CaCO 3 group (OP + TFRD + CaCO 3 group) and TFRD and CaCO 3 combined with N-acetyl cysteine group (OP + TFRD + CaCO 3 + NAC group). The rat model of OP was established by bilateral ovariectomy. The changes in bone mineral density (BMD), bone volume parameters and bone histopathology in the rats from each group were observed. The levels of serum reactive oxygen species, superoxide dismutase (SOD), malondialdehyde, glutathione peroxidase (GSH-Px), interleukin (IL)-6, IL-1β, TNF-α, and the levels of bone tissue runt-related transcription factor 2 (RUNX2), osteoprotegerin (OPG), osteocalcin (BGP), PI3K, p-PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR) and p-mTOR were measured in the rats of each group. The induction of OP was associated with a marked decrease in BMD, bone mineral content, bone volume fraction and trabecular thickness, and decreased serum levels of SOD and GSH-Px. Moreover, the expressions of RUNX2, OPG, BGP were downregulated and an upregulation of p-PI3K, p-AKT and p-mTOR were observed in osteoporotic rats. However, treatment with TFRD and CaCO 3 restored all the aforementioned parameters to almost normal values. Furthermore, the findings on histopathological evaluation were consistent with the biochemical observations. Taken together, the findings of the present study demonstrated that TFRD and CaCO 3 significantly increased the antioxidant capacity in rats with OP, increased BMD and reduced bone mineral loss, and may be useful for the prevention and treatment of OP.