Abstract The intelligent nanomachine usually has a control center to carry out self‐regulation. Unfortunately, most of the nanomaterials for chemodynamic therapy (CDT) do not have such a control center to sense and process the chemical or biological signals, which greatly weakens the selectivity and efficiency of CDT. To address this problem, here an intelligent nanomachine was constructed with a DNAzyme logic gate as the control center, and metal organic framework as the actuator. The well‐designed nanomachine showed an enhanced killing effect on cancer cells but posed no harm to normal cells, acquiring better selectivity than clinical chemotherapy drugs (doxorubicin and cisplatin). To the best of our knowledge, this is the first reported cell‐specific CDT by the guidance of DNAzyme logic gate. Our work highlights the great potential of DNAzymes in intelligent response networks, and extends the implementation of nanomachines in precision medicine.