Osteoporosis is a bone related disease that is characterised by bone loss that further increases the susceptibility to bone fractures and bone frailty due to disturbances in the micro-architecture of bone tissue. Fisetin (flavonoids) exhibited anti-inflammatory and antioxidative stress effects against various diseases. In this protocol, we make an effort to comfort the anti-osteoporosis effect of fisetin against ovariectomy (OVX) induced osteoporosis. A docking study of fisetin and alendronate on the estrogen (α and β) and vitamin D receptors was carried out. SaOS-2 (osteoblast like human) cells were used for the estimation of cell proliferation. The OVX induced OVX model was used and three doses of fisetin and alendronate was given to rats till 16 weeks. The hormone levels, bone turnover markers and biochemical parameters were estimated. Fisetin was docked into estrogen (α and β) and vitamin D receptors, resulting in stable complexes with lower binding scores. Fisetin significantly (p < 0.001) exhibited the induction of cell proliferation against the SaOS-2 cells. OVX induced osteoporosis rats exhibited a suppression of body weight and uterus index, after the Fisetin treatment. Fisetin treatment significantly (p < 0.001) improved the level of bone mineral content (BMC), bone mineral density (BMD) and biochemical parameters such as energy, maximum load, stiffness, young modules, maximum stress and reduced the level of 1,25(OH) 2 D3 and E 2 . Fisetin treatment significantly (p < 0.001) declined the level of phosphorus (P), calcium (Ca) and boosted the level of VitD. Fisetin treatment significantly (p < 0.001) reduced the malonaldehyde (MDA) level and enhanced the glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) level in the bone, intestine and hepatic tissue. Fisetin treatment suppressed the cytokines, RANKL/OPG ratio, receptor activator of nuclear factor-κB ligand (RANKL) and improved the level of osteoprotegerin (OPG). The findings suggest that fisetin could be a beneficial phytoconstituent for the treatment and prevention of postmenopausal osteoporotic complications.