Next-generation sequencing (NGS) technologies have revolutionized bone cancer research, enabling detailed insights into the genetic, transcriptional, and epigenetic layers of these malignancies. This overview discusses the pivotal role of NGS in enhancing the diagnosis, prognosis, and treatment of primary bone cancers such as osteosarcoma, chondrosarcoma, and Ewing sarcoma. By facilitating the identification of novel genetic mutations, gene fusions, and epigenetic alterations, NGS supports the development of personalized medicine approaches and targeted therapies, significantly impacting clinical outcomes. The utilization of various NGS platforms, including Illumina, SOLiD, and Ion Torrent, has provided comprehensive genomic profiles that inform targeted treatment strategies and enable early detection through liquid biopsies and circulating tumor DNA (ctDNA) analysis. Despite the profound clinical benefits, the integration of NGS into routine practice faces challenges such as technical limitations, complex data interpretation, and substantial infrastructure requirements. Future directions involve technological improvements, combinatorial omics approaches, and extensive validation through clinical trials to confirm the efficacy of NGS-guided interventions. These advancements promise to further enhance the precision and effectiveness of bone cancer management, offering hope for more tailored and effective therapeutic outcomes.