Osteoclasts are responsible for bone resorption caused by bone microstructural damage and bonerelated disorders. Evidence shows that tanshinone IIA (Tan-IIA), a traditional Chinese medicine, is used clinically as a drug for the treatment of cardiovascular and cerebrovascular diseases. However, the efficacy and mechanism underlying the effect of Tan-IIA on the viability of osteoclasts remain to be fully elucidated. The present study investigated the therapeutic effects of Tan-IIA on osteoblast differentiation and oxidative stress in vitro and in vivo. Cell viability was analyzed and oxidative stress was examined in the osteoblasts. Wnt1 sw/sw mice were used to investigate the therapeutic effects of Tan-IIA on spontaneous tibia fractures and severe osteopenia. The bone strength, collagen and mineral were examined in the tibia. Osteoblast activity was also analyzed in the experimental mice. The Tan-IIA-induced differentiation of osteoclasts and the mechanism of action were investigated in osteocytes. The data showed that Tan-IIA treatment improved cell viability. The data also demonstrated that Tan-IIA decreased the levels of H 2O 2, accumulation of reactive oxygen species and apoptosis of osteoblasts. Tan-IIA inhibited the deleterious outcomes triggered by oxidative stress. In addition, Tan-IIA inhibited the activation of nuclear factor (NF)-κB and its target genes, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase and cyclooxygenase 2, and increased the levels of TNF receptor-associated factor 1 and inhibitor of apoptosis protein-1/2 in the osteocytes. Furthermore, it was shown that Tan-IIA reduced the propensity to fractures and severe osteopenia in mice with osteoporosis. Tan-IIA also exhibited improved bone strength, mineral and collagen in the bone matrix of the experimental mice. It was found that the Tan-IIA-mediated benefits on osteoblast activity and function were through the NF-κB signaling pathway. Taken together, the data obtained in the present study suggested that Tan-IIA had protective effects against oxidative stress in osteoblastic differentiation in mice with osteoporosis by regulating the NF-κB signaling pathway.