Background: Currently, plenty of studies have demonstrated that lncRNAs can act as crucial roles during the progression of various tumors, including osteosarcoma (OS), and emerging evidences indicated that lncRNAs are abundant and stable in exosomes. The objective of this study is to reveal the dysregulated lncRNAs in OS plasma exosomes and explore their functions in OS. Materials and Methods: Microarray was performed to analyze dysregulated exosomal lncRNAs. Western blot, qRT-PCR assays, and Dual-luciferase reporter assay were used to verify the interaction among cancer susceptibility 15 (CASC15), miR-338-3p, and RAB14. Cck-8, colony formation assay, and transwell assay were performed to explore and characterize the effects of CASC15 on OS cells. Animal experiments were used to verify the effects of CASC15 in vivo. Results: Upregulated CASC15 was observed in OS plasma exosomes compared with control, and the same expression was observed in the OS tissues and cell lines. Further assays indicated that CASC15 knockdown could restrain the proliferation, migration, and invasion of OS cells, and inhibit the growth of OS in xenograft models. Furthermore, our results demonstrated CASC15 regulated OS progression via acting as miR-338-3p sponge, and RAB14 was a direct downstream target of miR-338-3p. Rescue experiments verified CASC15 promotes OS cell growth and metastasis by upregulating RAB14 expression. Conclusion: Overall, our findings indicate that CASC15 plays a key role in OS progression by targeting the miR-338-3p/RAB14 axis and can serve as a possible therapeutic target for OS patients.