<p>Osteosarcoma is a highly aggressive primary bone tumor of mesenchymal origin that predominantly affects children and adolescents. It is characterized by rapid growth and early metastasis, particularly to the lungs. Despite ongoing progress in conventional treatments such as surgical resection, chemotherapy, and radiotherapy, the five-year survival rate remains at 60%–70%, with significantly poorer outcomes in metastatic cases. In recent years, considerable advances have been made in basic research, clinical therapies, and diagnostic technologies; however, numerous challenges persist. This article provides a comprehensive review of recent breakthroughs in the molecular understanding, clinical management, and diagnostic innovation of osteosarcoma. We detail key findings in molecular signaling pathways, metabolic reprogramming, novel therapeutic agents like antibody–drug conjugates (ADCs) and combination strategies, as well as technological innovations in imaging and liquid biopsy. Furthermore, we discuss current unmet clinical needs, including chemoresistance and metastasis, and outline future directions emphasizing multi-target synergistic interventions, modulation of the metabolism–immune axis, and cross-disciplinary collaboration. Continued patient-centered efforts integrating multimodal diagnostics and personalized therapeutic approaches are essential to improve outcomes for patients with this aggressive malignancy.</p>