Papillary thyroid cancer (PTC) is an endocrine malignancy whose incidence has increased rapidly worldwide. Exosome-miR-655-3p was down-regulated in patients with PTC. However, the effect and molecular mechanism of exosome-miR-655-3p in PTC was indistinct until now. Our study found that exosome-miR-655-3p was decreased in serum of PTC patients. Overexpression of miR-655-3p with mimics significantly shrunk the cell viability, reduced the number of chemotactic and invasive PTC cells. Besides, the proportion of CD163 positive cells and the expression of markers of M2 subtype macrophages was markedly decreased when mononuclear macrophage THP-1 was cultured with exosomes of miR-655-3p mimics. Oppositely, the inhibitor of miR-655-3p exacerbated growth, chemotaxis and invasion of PTC cells, and enhanced the M2 subtype macrophages. Structurally, miR-655-3p could target the 3’ untranslated region (3’UTR) of CXCR4 and restrict the expression of CXCR4. In Xenograft tumor experiment, upregulated exosome-miR-655-3p effectively inhibited the growth of tumor and reduced the expression of CXCR4, Ki67 and CD163 in vivo. In summary, exosomal miR-655-3p inhibited growth, invasion and macrophage M2 polarization through targeting CXCR4 in papillary thyroid carcinoma. Regulating exosome-miR-655-3p/CXCR4 may be a potential treatment strategy for PTC.