Metastasis remains the primary cause for mortality of breast cancer. Despite advances in current therapeutic agents, patients with metastatic breast cancer still have poor prognoses. Tumor hypoxia, a key microenvironment factor, is emerging as an attractive target to prevent metastasis and is also involved with resistance to phototherapy. Here, we show an effective nanotherapeutic approach based on manganese dioxide-coated polydopamine nanocarriers to trigger robust anti-tumor and anti-metastasis responses against metastatic breast cancer by supplemental oxygenation and multimodal imaging-guided phototherapies. In cancer cells, the produced oxygen by the developed nanoplatform decreases the expression of hypoxia-inducible factors 1α to inhibit tumor metastasis, and enhances the efficacy of photodynamic therapy. This nanotherapeutic approach enables the combined photodynamic/ photothermal treatments with great inhibition on cell migration and invasion in vitro. Moreover, the nanotherapeutics effectively suppresses primary tumor progress and inhibits lung metastasis in vivo in a breast cancer mouse model with satisfying biosafety. This study suggests that the tumor hypoxia-targeting nanotherapeutics have great potential for preventing and treating metastatic cancers.