Background/Aim: Sorafenib has been reported to show anti-osteosarcoma (anti-OS) efficacy by inhibiting metastasis; however, a phase II trial suggested that further combination with other agents could be necessary to achieve permanent remission. Herein, we aimed to identify whether amentoflavone, an abundant natural bioflavonoid found in many medicinal plants, can improve the treatment efficacy of sorafenib in OS. Materials and Methods: Cell viability, metastasis, apoptosis, and nuclear translocation of NF-ĸB after amentoflavone combined with sorafenib were assayed by MTT, transwell migration/invasion, western blotting, flow cytometry, and immunofluorescence staining, respectively. Results: The sorafenib-induced cytotoxicity and apoptosis of U-2 OS was enhanced by combining treatment with QNZ (NF-ĸB inhibitor) or amentoflavone. NF-ĸB nuclear translocation, NF-ĸB phosphorylation, and metastasis capacity of U-2 OS cells were inhibited by amentoflavone combined with sorafenib. Conclusion: Amentoflavone may sensitize OS to sorafenib treatment by inducing intrinsic and extrinsic apoptosis and inhibiting ERK/NF-ĸB signaling transduction.