Here, a novel “Three‐in‐One” Cu‐based metal‐organic framework nanozyme with peroxidase‐like (POD‐like) activity has been successfully developed, aiming to promote CRC cell death by dual targeting of oxidative stress and copper ion homeostasis, which could promote CRC cell death via apoptosis and cuproptosis, and facilitate hypoxia‐inducible factor 1α (HIF‐1α) degradation, leading to the reversal of chemoresistance in tumor therapy. This evidence concerns the gene HIF1A and neoplasm.