Sonodynamic therapy (SDT) has emerged as a promising strategy for neuroblastoma treatment, leveraging ultrasound to induce the production of reactive oxygen species (ROS) at tumor sites, thereby enhancing the efficacy of immunotherapy. However, a major challenge in SDT is the efficiency of ROS generation, particularly in the context of hypoxia within the tumor microenvironment. Herein, inspired by the natural peroxidase, an imide-linked metal-phthalocyanine-based conjugated organic polymer (COP) (COPTPcFe) has been designed with a well-defined π-conjugated nanostructure and peroxidase-mimetic atomic Fe-N sites for sonochemodynamic immunotherapy against neuroblastoma. This work demonstrates that COPTPcFe can efficiently produce potent ROS (•OH and •O2 -) by utilizing localized H2O2 and the effects of ultrasound, thereby achieving efficient and synergistic tumoricidal activity. Notably, the highly π-conjugated structure endows COPTPcFe with excellent electron transport capabilities, enabling rapid catalysis of H2O2 to O2, thus alleviating the hypoxic conditions within tumors. Moreover, by encapsulating COPTPcFe with neuroblastoma cell membranes, this study achieveshomologous targeting of tumor cells and tissues, leading to efficient accumulation within tumor cells, mitochondrial disruption, and apoptosis. Additionally, the proposed sonochemodynamic immunotherapy effectively activates natural killer cells and reverses the immunosuppressive tumor microenvironment, thereby alleviating hypoxia and significantly enhancing the therapeutic efficacy of neuroblastoma treatment.© 2025 Wiley‐VCH GmbH.