Postmenopausal osteoporosis severely jeopardizes human health. Seeking for therapeutic drugs without side effects is of great necessity. Our study was designed to investigate whether resveratrol, an agonist of SIRT1, could have favorable effect on osteoporosis and to explore the underlying mechanisms. Rat osteoporosis model (ovariectomy group, OVX) was established by bilateral ovariectomy. Three different doses of resveratrol were used: 5 mg/kg/d (low-dosed, RES^LD), 25 mg/kg/d (medium-dosed, RES^MD), and 45 mg/kg/d (high-dosed, RES^HD). Results showed that RES^LD did not show any significant effect on OVX alterations, while RES^MD and RES^HD significantly elevated the decreased bone mineral density induced by osteoporosis (RES^MD 0.205±0.023, RES^HD 0.214 ± 0.053 vs. OVX 0.165 ± 0.050 g/cm² respectively; P < 0.05). Serum markers alkaline phosphatase (ALP) and osteocalcin were moderately restored by resveratrol. Moreover, resveratrol improved bone structure in OVX rats, demonstrated by hematoxylin-eosin staining and micro-computed tomographic results. In vitro results revealed that resveratrol promoted osteoblast differentiation of bone marrow mesenchymal stromal cells, evidenced by the increase of ALP generation and mRNA expression of collagen 1 (P < 0.05; RES^MD, RES^HD vs. control group). SIRT1 gene silencing by siRNA transfection blocked these beneficial effects of resveratrol (P < 0.05; RES + SIRT1^KD vs. RES^HD). Western blot results showed that resveratrol activated SIRT1 and subsequently suppressed the activity of NF-κB with decreased expression level of p-IκBα and NF-κB p65 (P < 0.05). Our findings verified the effects of specific dosed resveratrol on postmenopausal osteoporosis through osteoblast differentiation via SIRT1-NF-κB signaling pathway. This study suggested the therapeutic potential of resveratrol against osteoporosis and stressed the importance of effective doses.