Here an excellent trimodality imaging‐guided synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT) is proposed. To this end, a mixed‐metal Cu/Zn‐metal‐organic framework (MOF) is first assembled at room temperature on a nano‐scale. Interestingly, heating the MOF results in a Cu+/2+‐coexisting hollow porous structure. Subsequent heating treatment is used to integrate Mn2+ and MnO2 in the presence of manganese(II) acetylacetonate. The hollow composite achieves efficient loading of a photosensitizer, indocyanine green (ICG). Under laser irradiation, the aggregated ICG achieves photothermal imaging and PTT. Once released in the tumor site, ICG exhibits fluorescence imaging and PDT capacity. Cu+/Mn2+ ions perform Fenton‐like reaction with H2O2 to produce cytotoxic •OH for the enhanced CDT. Cu2+/MnO2 scavenge glutathione to improve the reactive oxygen species‐based therapy, while the formed Mn2+ ions enable “turn on” magnetic resonance imaging. Significantly, O2 is produced from the catalytic decomposition of endogenous H2O2 to improve ICG‐mediated PDT. Moreover, photothermal‐induced local hyperthermia accelerates •OH generation to enhance CDT. This synergistic drug‐free antitumor strategy realizes high treatment efficacy and low side effects on normal tissues. Thus, this mixed‐metal MOF is an efficient strategy to realize hollow structures for multi‐function integration to improve therapeutic capacity. A mixed‐metal metal‐organic framework strategy is proposed to form a hollow structure, integrating mixed‐metals with mixed‐valences, and loading indocyanine green. The composite enables photothermal/magnetic resonance/fluorescence imaging‐guided photothermal therapy, photodynamic therapy, and chemodynamic therapy. High therapeutic efficiency and negligible side effects are realized as non‐drug treatment.