Concurrent treatment of tumor recurrence and bone defects after surgical resection of osteosarcoma remains a clinical challenge. Combination therapy based on local drug delivery systems shows great promise in the treatment of osteosarcoma. In this study, curcumin modified polydopamine nanoparticle loaded silk fibroin doped with nano-hydroxyapatite (CM-PDA/SF/nHA) nanofibrous scaffolds were developed to induce bone defect regeneration and chemo-photothermal synergistic effects against osteosarcoma. These scaffolds exhibited good photothermal conversion efficiency and photostability. Moreover, the results of ALP staining and alizarin red S (ARS) staining indicated that the CM-PDA/SF/1%nHA scaffolds had the most obvious promotion effect on early osteogenic differentiation. The results of and anti-osteosarcoma activity showed that the CM-PDA/SF/1%nHA scaffolds exhibited higher anti-osteosarcoma activity compared to the control and SF scaffolds. In addition, the CM-PDA/SF/1%nHA scaffolds could promote the proliferation and differentiation of bone marrow mesenchymal stem cells and new bone production . Thus, these results suggested that the CM-PDA/SF/1%nHA scaffolds could improve bone defect regeneration and achieve chemo-photothermal synergistic effects against osteosarcoma.