We previously showed that the chemokine CCL2 can recruit macrophages (Mφs) to the bone marrow (BM) in multiple myeloma (MM) and that myeloma-associated Mφs are important in drug resistance. Here, we explore the role of increased CCL2 expression in the BM microenvironment of MM and elucidate the underlying mechanism. Our results show that CCL2 expression is associated with the treatment status of MM patients. Mφs interact with MM cells and further upregulate their expression of CCL2. These increased level of CCL2 polarizes Mφs toward the M2-like phenotype and promotes Mφs to protect MM cells from drug-induced apoptosis. Mechanistically, CCL2 upregulated the expression of the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in Mφs. MCPIP1 mediates Mφs' polarization and protection via dual catalytic activities. Additionally, we found that CCL2 induces MCPIP1 expression via the JAK2-STAT3 signaling pathway. Taken together, our results indicate that increased CCL2 expression in MM patients' BM polarizes Mφs toward the M2-like phenotype and promotes the protective effect of Mφs through MCPIP1, providing novel insight into the mechanism of Mφs-mediated drug resistance in MM.