Currently, photodynamic therapy (PDT) has been greatly restricted by the tumor hypoxia. To overcome this problem, here, we designed a novel nanoplatform, Fe3O4@MIL-100(Fe)-UCNPs (abbreviated as FMU), in which UCNPs were acted as energy transducers to transfer NIR-UV/vis light to the heterojunction photosensitizer Fe3O4@MIL-100(Fe) (abbreviated as FM), producing cytotoxic hydroxyl radicals ((OH)-O-center dot) with a high tumor cell oxidation capability independent of tumor oxygen. In particular, the recombination of electrons and holes has been markedly inhibited due to the formation of heterojunctions in the interfaces between MIL-100(Fe) and Fe3O4 nanoparticles, thus greatly enhancing the capability for (OH)-O-center dot production. Meanwhile, the Fe3+/Fe2+ ions were used to provide the photochemotherapy (PCT) effect based on the photo-Fenton reaction, thereby achieving combined PDT and PCT synergistic therapy. The outstanding antitumor efficiency was verified by in vivo and in vitro assays, and it was shown that the therapeutic process can be monitored by computed tomography (CT) and upconversion luminescence (UCL) imaging, suggesting that the resultant nanoplatform has potential for use in imaging-guided cancer therapy.