BACKGROUND Osteoporosis is a common disorder leading to bone loss. At present, the treatment options available for the management of osteoporosis are limited. The present investigation evaluated the protective effect of fangchinoline against osteoporosis and also postulates the possible mechanism of action. MATERIAL AND METHODS Osteoporosis was induced by subcutaneously injecting prednisolone (2.5 mg/pellet) for 4 weeks. Fangchinoline 1, 3 and 10 mg/kg was given intraperitoneally for the period. Protective effects of fangchinoline were assessed by estimating microarchitectural parameters and bone mineral density (BMD) in the vertebrae tissues, and biochemical parameters were also determined in the serum of rats with prednisolone-induced osteoporosis. Moreover, gene expression of microtubule-associated protein 1A/1B-light chain 3 (LC3), B cell lymphoma 2 (Bcl-2), caspase-3, bone morphogenetic protein 2 (BMP2), Beclin-1, autophagy-related 5 (ATG-5), Runt-related transcription factor 2 (RUNX-2), and receptor activator of nuclear factor kappa-b ligand (RANKL) protein in the vertebrae tissue were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay. RESULTS There was a significant (p<0.01) decrease in the BMD and microarchitectural parameters in the vertebrae tissue of the fangchinoline-treated group compared to the prednisolone group. We also found that treatment with fangchinoline attenuated the altered expressions of LC3, Bcl-2, caspase-3, BMP2, Beclin-1, ATG-5, RUNX-2, and RANKL protein in the prednisolone-induced osteoporosis rats. Moreover, levels of biochemical parameters were attenuated in the serum of fangchinoline-treated and prednisolone-induced osteoporosis rat. Histopathology revealed that the apoptosis of osteoblasts was decreased in the fangchinoline-treated group compared to the prednisolone group of rats. CONCLUSIONS Fangchinoline inhibits apoptosis of osteoblasts and protects against bone loss in prednisolone-induced osteoporosis rats by inducing autophagy.