The generation of singlet oxygen (¹O₂) during photodynamic therapy is limited by the precise cooperation of light, photosensitizer, and oxygen, and the therapeutic efficiency is restricted by the elevated glutathione (GSH) levels in cancer cells. Herein, we report that an ultrathin two‐dimensional metal–organic framework of Cu‐TCPP nanosheets (TCPP=tetrakis(4‐carboxyphenyl)porphyrin) can selectively generate ¹O₂ in a tumor microenvironment. This process is based on the peroxidation of the TCPP ligand by acidic H₂O₂ followed by reduction to peroxyl radicals under the action of the peroxidase‐like nanosheets and Cu²⁺, and their spontaneous recombination reaction by the Russell mechanism. In addition, the nanosheets can also deplete GSH. Consequently, the Cu‐TCPP nanosheets can selectively destroy tumor cells with high efficiency, constituting an attractive way to overcome current limitations of photodynamic therapy.