Chemodynamic therapy (CDT) has been limited by the tumor microenvironment, such as the low concentration of hydrogen peroxide (H2O2). The combination of therapeutic strategies that increase H2O2 with CDT can synergistically enhance the therapeutic effect. Herein, a novel supramolecular PEG-DNA-ferrocene nanogel that can codeliver glucose oxidase (GOx) and the hypoxia-activable prodrug tirapazamine (TPZ) was developed to synergistically amplify CDT via cascade reactions. The DNA nanogel was size-controllable and DNase I-responsive and exhibited good biocompatibility. Induced by oxygen consumption and H2O2 generation in the catalytic reaction of GOx, the drugs TPZ and ferrocene in the nanogel underwent the hypoxia-based reaction and the Fenton reaction, respectively. The vitro model tests, intracellular ROS test, MTT experiments, and DNA damage assay demonstrated that the H2O2-based cascade Fenton reaction and the hypoxia-based cascade reaction obviously increased ·OH generation and promoted the apoptosis of cancer cells. This cascade supramolecular nanoplatform provided a promising therapeutic strategy to synergistically amplify CDT.