Photodynamic therapy (PDT) is quickly developing as a hopeful cancer treatment. However, hypoxic tumors, poor targeting, and photosensitizers (PS) aggregation limited the efficiency of PDT. Here, we report a hyaluronic acid (HA)-modified CeO-nanoparticle-decorated metal-organic framework (PCN-224@CeO-HA) to enhance PDT and achieve targeted treatment. CeO catalyzes HO to produce O to solve hypoxia problems. HA could target the CD44 receptor, which is highly expressed on the tumor cell membranes. The growth of tumor cells 4T1 and MCF-7 was controlled distinctly after being incubated with PCN-224@CeO-HA under laser irradiation, while the survival ability of normal cell LO2 was nearly unchanged. Importantly, PCN-224@CeO-HA could be effectively aggregated within the tumor area after 12 h of injection, and the tumor growth was remarkably inhibited under laser irradiation. PCN-224@CeO-HA presented good biocompatibility and an excellent antitumor effect, providing a new strategy to produce O for enhanced PDT.