Tumor recurrence and a lack of bone-tissue integration are two critical concerns in the surgical treatment of osteosarcoma. Thus, an advanced multifunctional therapeutic platform capable of simultaneously eliminating residual tumor cells and promoting bone regeneration is urgently needed for efficient osteosarcoma treatment. Herein, to thoroughly eliminate tumors and simultaneously promote bone regeneration, an intelligent multifunctional therapeutic scaffold has been engineered by integrating microwave-responsive zeolitic imidazolate framework 8 (ZIF-8) nanomaterials loaded with a chemotherapeutic drug and an immune checkpoint inhibitor onto 3D-printed titanium scaffolds. The constructed scaffold features distinct microwave-thermal sensitization and tumor microenvironment-responsive characteristics, which can induce tumor immunogenic death by microwave hyperthermia and chemotherapy. Orthotopic implantation of the nanocomposite scaffold results in an enhanced immune response against osteosarcoma that may effectively inhibit tumor recurrence through synergistic immunotherapy. During long-term implantation, the zinc ions released from the degradation of ZIF-8 can induce the osteogenic differentiation of stem cells. The porous structure and mechanical properties of the 3D-printed titanium scaffolds provide a structural microenvironment for bone regeneration. This study provides a paradigm for the design of multifunctional microwave-responsive composite scaffolds for use as a therapy for osteosarcoma, which could lead to improved strategies for the treatment of the disease.