Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, with over 3.4 per million cases each year worldwide. It is a very aggressive tumor that often metastasizes, especially in the lungs, and has a 5-year survival rate around 70% for localized malignancies. The current treatment consists of surgery with adjuvant chemotherapy involving a combination of different agents, but OS can develop multidrug resistance. Moreover, chemotherapy has major drawbacks such as cardiotoxicity, neurotoxicity or nephrotoxicity. Nanotechnology has been proposed as a novel and promising approach for OS treatment to overcome the limitations of chemotherapy and to guarantee a better survival rate of patients.