Nanotechnology has recently become popular due to its potential for biomedical applications, especially for cancer treatment. Nanotechnology, featuring responsiveness to stimuli and stable drug release, has been widely used for the delivery of chemotherapeutic drugs, which are commonly used in the treatment of osteosarcoma. Smart stimuli-responsive nanotechnology is expected to improve the treatment of osteosarcoma. Herein, we focus on the latest research on nanomaterials in treating osteosarcoma that respond to internal and external stimuli. We also discuss nanocarriers with targeting ligands and the use of smart nanotechnology to partially reverse the multidrug resistance of osteosarcoma.