The limited light penetration depth and tumor hypoxia are two natural shortcomings of photodynamic therapy (PDT). Overcoming these two issues within a single system is still a great challenge. Herein, photosensitizer (PS)-loaded and PEG-modified MnFe2O4-decorated large-pore mesoporous silica-coated β-NaYF4:20%Yb,2%Er@β-NaYF4 upconversion nanoparticles (UCMnFe-PS-PEG) as excellent PDT agents are successfully prepared for NIR light-mediated and O2 self-sufficient PDT. The large mesoporous structure observably increases PS loading efficiency (11.33 wt%) and the green luminescence from upconversion nanoparticles activated by NIR is able to activate PSs to generate ROS effectively. In addition, sub-10 nm MnFe2O4 nanoparticles work as a Fenton catalyst to generate O2in situ. In vivo experiments further prove that UCMnFe-PS-PEG not only provides magnetic guidance to the tumor, but also overcomes tumor hypoxia and dramatically enhances PDT efficiency. Furthermore, in vivo MR and UCL imaging are performed for accurate cancer therapy. We believe that the successful construction of the multifunctional UCMnFe-PS-PEG provides more revelations for developing advanced nano-drug systems for cancer therapy.