Osteosarcoma (OS) is one of the most common malignant bone tumors in childhood and adolescence. Although great efforts have been made in therapeutic methods for OS, the prognosis is not yet satisfactory and the underlying molecular mechanisms of OS pathogenesis have not been fully explored. Meanwhile, non-coding RNAs, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have long been investigated due to their roles as key players in regulating various biological and pathological processes, such as proliferation, apoptosis, cell-cycle, migration, invasion, metastasis, EMT and drug resistance, through targeting their mRNAs transcriptionally or posttranscriptionally. Although, numerous studies have confirmed a complex cross-regulation among lncRNAs, miRNAs and mRNAs, the underlying molecular mechanism has not been elucidated. In this review, we comprehensively summarized the latest research progress of the regulatory relationship among lncRNAs, miRNAs and mRNAs, and highlighted the role of lncRNA-miRNA-mRNA axis in the development of OS to provide novel approaches for cancer diagnosis and treatment.