Osteoporosis is a skeletal disorder that is common in postmenopausal women. It is characterized by deteriorated bone mass and microarchitecture. In this study, we aimed to explore the effects and molecular mechanisms of resveratrol and mesenchymal stem cell (MSC) individual and combined treatment in management of osteoporosis in ovariectomized rats. Our results demonstrated that treatment of ovariectomized rats with resveratrol or MSCs improved bone mass and microstructure as indicated by increased bone mineral content and density. Moreover, resveratrol and MSCs stimulated osteogenesis as shown by increased levels of osteogenic markers such as runt-related transcription factor 2 (RUNX2). In addition, resveratrol and MSCs inhibited adipogenesis and osteoclastogenesis as indicated by the suppression of the adipogenic marker, peroxisome proliferator-activated receptor gamma (PPARγ) and the osteoclastogenesis marker, receptor activator of nuclear factor-κB ligand (RANKL). Mechanistically, our results showed that management of osteoporosis in resveratrol or MSC treated rats was achieved by activating two signaling pathways, sirtuin 1 (SIRT1) and wingless-related MMTV integration site (Wnt). Finally, the combination of resveratrol and MSCs was more effective in increasing bone mass and improving osteoporosis than individual treatments., (Copyright © 2021 Elsevier Inc. All rights reserved.)