Osteosarcoma is a rare malignancy; however, it is still the most common primary bone tumor in adolescents and young adults. Chemotherapy improves survival indubitably in osteosarcoma; nevertheless, the concern is the stagnant progress since the last several decades. There are a handful of active agents and unresolved issues, especially in choosing the ideal chemotherapy regimen. The oncology community is in equipoise regarding the position of high-dose methotrexate (HDMTX), mandatory or adjunct. The choice of therapy becomes widely relevant, including in low- and middle-income countries (LMIC), where HDMTX administration brings additional complexities. Research into novel non-HDMTX-based protocols adapted to the available resources is pivotal in improving disease outcomes, especially in LMIC. The current review focuses on real-world challenges in decision-making and provides a comprehensive overview of the evolution of treatment protocols in LMIC.