Photodynamic therapy (PDT) that utilizes apoptosis induced by reactive oxygen species (ROS) has received extensive attention in practical cancer therapy. However, the hypoxic microenvironment of solid tumors significantly limits the efficacy of therapy. Approaches that overcome the barriers to PDT in hypoxic conditions by simultaneously producing ROS exogenously and improving the oxygenation of tumors have never been studied. Herein, an activatable ROS platform was designed that uses the high reactivity of peroxidase-like Fe3O4 toward endogenous hydrogen peroxide (H2O2) to concurrently generate ˙OH as a therapeutic agent and provide O2 for oxygen-dependent PDT. Multifunctional chitosan-encapsulated Fe3O4 nanoparticles modified with CuS and porphyrin (FCCP NPs) were fabricated to achieve multimodal imaging and synergetic therapy. The FCCP NPs possess enhanced intrinsic peroxidase mimetic activity to produce ROS and O2 from endogenous H2O2. Multimodal imaging in vivo, including photoacoustic imaging (PAI), magnetic resonance imaging (MRI), photoluminescence imaging (PLI), and photothermal imaging (PTI), exploits the tumor-targeting property of FCCP NPs upon intravenous injection. It can induce cancer cell death with remarkable efficiency both in vitro and in vivo via synergetic treatment with PDT and photothermal therapy (PTT). This study demonstrates the promise of the activatable generation of ROS and O2 for PDT with nanotechnology to overcome a current deficiency in cancer therapies.