Approximately 70% of patients with advanced breast cancer develop bone metastases, accompanied by complications, such as bone pain, fracture, and hypercalcemia. However, our understanding of the molecular mechanisms that govern this process remains fragmentary. Osterix (Osx) is a zinc finger-containing transcription factor essential for osteoblast differentiation and bone formation. Here, we identified the functional roles of Osx in facilitating breast cancer invasion and bone metastasis. Osx upregulation was associated with lymph node metastasis and was negatively prognostic for overall survival. Knockdown of Osx inhibited invasion of breast cancer and osteolytic metastasis by downregulating MMP9, MMP13, VEGF, IL-8, and PTHrP, which are involved in invasion, angiogenesis, and osteolysis; overexpression of Osx had the opposite effect. Moreover, MMP9 was a direct target of Osx and mediated the Osx-driven invasion of breast cancer cells. Together, our data showed that Osx facilitates bone metastasis of breast cancer by upregulating the expression of a cohort of genes that contribute to steps in the metastatic cascade. These findings suggest that Osx is an attractive target for the control of bone metastasis of breast cancers.