Background Osteosarcoma (OS) immune environment is complexed and the immune factors‐related to OS progression need to be explored. Tumor‐associated macrophages (TAMs) are regarded as immune suppressive and tumor‐promoting cells. However, the underlying mechanisms through which TAMs function are still fragmentary. Here, we aim to explore the underlying mechanisms by which TAMs regulate OS progression. Methods TAMs from OS tissues were isolated by flow cytometry. Exosomes derived from TAMs were separated using ultracentrifugation and western blotting. Transmission electron microscopy (TEM), and flow cytometry were constructed to characterize TAMs‐derived exosomes. Additionally, the differential MicroRNAs (miRNAs) and genes were detected through RNA sequencing, and further validated using real‐time PCR (RT‐PCR). OS cell metastasis ability was assessed using transwell invasion and scratch wound healing assays. MiRNAs mimic and lentiviral vectors were utilized to explore the effects on OS progression. Results Exosome secreted by TAMs accelerated the OS metastasis. Let‐7a level was upregulated in TAMs derived exosomes, which downregulated C15orf41 by targeting 3′‐untranslated region (UTR). Furthermore, overexpressing let‐7a enhanced invasion and migration by blocking the transcription of C15orf41. In consistent, up‐regulating let‐7a promoted OS progression and made the prognosis to be worse, which can be reversed by C15orf41 overexpression. Conclusion This study highlighted the critical role of TAMs‐derived exosomes in OS progression and explored the potential value of the let‐7a/C15orf41 axis as an indicator or target for OS.