The intensive investigation of chemodynamic therapy (CDT) for tumor eradication revealed that the therapeutic effects of this ROS-mediated therapy are limited by endogenous reductants and inefficient Fenton-like reactions. In this study, we developed a new Fe/Cu-AuNP-PEG nanocomposite to enhance CDT and provide a synergistic treatment for tumors. The Fe/Cu-AuNP-PEG nanocomposite demonstrated effective ˙OH production and high photothermal conversion efficiency under 808 nm illumination, which promoted the ˙OH production, thereby enhancing the CDT efficacy and exhibiting a synergistic treatment for cancer. More importantly, the Fe/Cu-AuNP-PEG nanocomposite showed the ability to deplete GSH and catalyze glucose to generate H2O2, which facilitated the Fenton-like reaction and reduced the antioxidant properties of tumors, further improving the efficacy of CDT. Therefore, the Fe/Cu-AuNP-PEG nanocomposite, with horseradish peroxidase-like, glutathione peroxidase-like, and glucose oxidase-like activities, is a promising anti-tumor agent for integrating enhanced CDT and photothermal therapy (PTT) with the enhancement of synergistic therapeutic effects.