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Abstract Although the interaction between tumor cells and tumor‐associated macrophages (TAMs) has been widely studied; however, the mechanism of osteosarcoma cells in regulating the polarization of TAMs remains unclear. Exosomes from SAOS‐2 cells were isolated and validated by electron microscopy and Western blot. Transfection of indicated plasmids was applied to modify the expressions of miR‐181a‐5p and RAR‐related orphan receptor alpha (RORA). Flow cytometric analysis was carried out to analyze M1/M2 macrophage polarization. Quantitative real‐time PCR was performed to determine the levels of miR‐181a‐5p and RORA. Protein levels of CD63, CD81, RORA, CD163, CD206, IL‐10, CXCL10, and IL‐1β were evaluated by Western blot. The direct interaction of miR‐181a‐5p and RORA was validated by dual‐luciferase activity assay. The expression of miR‐181a‐5p was upregulated in osteosarcoma tissues and presented in SAOS‐2‐derived exosomes. SAOS‐2‐derived exosomes promoted the polarization of M2 macrophages by transferring miR‐181a‐5p. In addition, RORA was downregulated in osteosarcoma tissues and showed a negative correlation with miR‐181a‐5p. RORA was found to be the downstream target of miR‐181a‐5p in SAOS‐2 cells. Inhibition of RORA reversed the effects of miR‐181a‐5p knockdown on the polarization of M2 macrophages. The results showed that exosomal miR‐181a‐5p derived from osteosarcoma cells induced polarization of M2 macrophages via targeting RORA.