Objective To investigate the protective effect and its mechanism of resveratrol (RES) on rats with osteoporosis. Methods A total of 72 clean grade female SD rats were randomly divided into six cohorts: control cohort, osteoporosis model cohort, estrogen pretreated cohort, low, median and high dosage RES pretreated cohorts. Except for rats in the control cohort, rats in other cohorts were treated by bilateral oophorectomy and pretreated with 17β-E2 and different dosage of resveratrol respectively, ranging from 1 to 12 weeks after operation. The blood parameters associating with osteoporosis were tested. Morphological observation of bone tissue was performed by HE staining under a microscope. Bone mineral density was measured by a dual-energy X-ray absorptiometry. The mRNA expression level of antioxidant enzymes (gpx1, trx1 and γ-gt) were assayed by RT-PCR. Results Serum calcium, serum phosphate, ALP and TRAP increased obviously, but estrogen and calcium level in serum decreased sharply in the animal model. The bone tissue of the model manifested typical osteoporosis characteristics, and the expression of antioxidant enzymes was at a low level. After treated with estrogen or different dosages of resveratrol, the parameters and phenotypes mentioned above were almost close to the control cohort.Conclusion Resveratrol, likely estrogen, can maintain a balance of bone formation and absorbance, which is critical to the homeostasis of bone, antagonizing the osteoporosis pathology progression. This protective mechanism is associated with the expression and activity of antioxidant