Osteoporosis, an age-related metabolic bone disease, is mainly caused by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. At present, there are many osteoporosis drugs that can promote bone formation or inhibit bone resorption. However, there were few therapeutic drugs that can simultaneously promote bone formation and inhibit bone resorption. Oridonin (ORI), a tetracyclic diterpenoid compound isolated from Rabdosia rubescens, has been proved to have anti-inflammatory, anti-tumor effects. However, little is known about the osteoprotective effect of oridonin. Thioacetamide (TAA) is a common organic compound with significant hepatotoxicity. Recent studies have found that there was a certain association between TAA and bone injury. In this work, we investigated the effect and mechanism of ORI on TAA-induced osteoclastogenesis and inhibition of osteoblast differentiation. The results showed that TAA could promote the osteoclastogenesis of RAW264.7 by promoting the MAPK/NF-κB pathway, and also promoted p65 nuclear translocation and activated intracellular ROS generation, and ORI can inhibit these effects to inhibit TAA-induced osteoclastogenesis. Moreover, ORI can also promote the osteogenic differentiation pathway and inhibit adipogenic differentiation of BMSCs to promote bone formation. In conclusion, our results revealed that ORI, as a potential therapeutic drug for osteoporosis, could protect against TAA-induced bone loss and TAA-inhibited bone formation.