Chemodynamic therapy (CDT) has been critically challenged by insufficient H2O2 in cancer tissues and inefficient reactive oxygen species (ROS) production. Herein, we have reported the facile synthesis of an efficient ROS generator (GOx@Pd@ZIF-8) that exerts synergistic anticancer activity by blocking glucose metabolism and producing ROS. Glucose oxidase (GOx) and palladium (Pd) cube nanozymes were incorporated in zeolitic imidazolate framework-8 (ZIF-8) by biomimetic mineralization. Systematic characterization indicated the successful entrapment and embedding of GOx and Pd during ZIF-8 crystal growth. The GOx@Pd@ZIF-8 composite showed favorable catalytic glucose activity and stable ROS production. In vitro experiments showed that the GOx@Pd@ZIF-8 composite effectively inhibited cancer cell proliferation, invasion, and migration and promoted apoptosis through the ROS-mediated signaling pathway, which was further confirmed by bioinformatics analyses of RNA-seq data obtained from in vitro experiments. Furthermore, the GOx@Pd@ZIF-8 composite inhibited tumor growth with few to no side effects on other tissues in vivo. This work provides a novel antitumor strategy involving the construction of a stable and highly active ROS generator that shows promise for the treatment of solid cancers.