Chemodynamic therapy (CDT), leveraging Fenton reactions to generate hydroxyl radicals (•OH) from intracellular hydrogen peroxide (H2O2), offers a promising cancer treatment strategy due to its high specificity and low systemic toxicity. However, the targeted delivery of •OH-producing prodrugs using covalent organic frameworks (COFs) remains a significant challenge. Here, we report a mitochondria-targeted COF-based nano prodrug, COF-31@P, designed for enhanced CDT efficacy. COF-31@P is composed of a Fenton-like copper complex and the hydrogen peroxide enzyme inhibitor 3-amino-1,2,4-triazole (3-AT), linked via disulfide bonds that are selectively cleaved by tumor-specific glutathione (GSH). This cleavage triggers the release of active components, resulting in robust •OH generation and effective eradication of cancer cells. The platform demonstrates precise mitochondrial targeting, high therapeutic efficiency, and excellent biocompatibility in vivo. By combining organelle targeting and multi-synergistic •OH generation production, our COF-31@P represents a significant advancement in CDT and holds strong potential for clinical translation.© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley‐VCH GmbH.