Reactive oxygen species-mediated therapeutic strategies, including chemodynamic therapy (CDT) and photodynamic therapy (PDT), have exhibited translational promise for effective cancer management. However, monotherapy often ends up with the incomplete elimination of the entire tumor due to inherent limitations. Herein, we report a core-shell-structured PdBi@CeO-ICG (PBCI) nanoplatform constructed by a facile and effective strategy for synergistic CDT, PDT, and photothermal therapy. In the system, both PdBi and CeO constituents exhibit peroxidase- and catalase-like characteristics, which not only generate cytotoxic hydroxyl radicals (OH) for CDT but also produce O in situ and relieve tumor hypoxia for enhanced PDT. Furthermore, upon 808 nm laser irradiation, PdBi@CeO and indocyanine green (ICG) coordinately prompt favorable photothermia, resulting in thermodynamically amplified catalytic activities. Meanwhile, PBCI is a contrast agent for near-infrared fluorescence imaging to determine the optimal laser therapeutic window in vivo. Consequently, effective tumor elimination was realized through the above-combined functions. The as-synthesized unitary PBCI theranostic nanoplatform represents a potential one-size-fits-all approach in multimodal synergistic therapy of hypoxic tumors.