Mesenchymal stem cell (MSC) treatment of osteoarthritis is currently a frontier and focus of research. Studies have demonstrated that macrophages play a significant role in the treatment of osteoarthritis with MSCs. The polarization of macrophages towards the selectively activated macrophage (M2 phenotype), promoted by MSCs, is a crucial mechanism for the treatment of osteoarthritis. This mechanism involves the regulation of certain proteins and miRNAs secreted by MSCs. In addition, MSC paracrine substances (such as exosomes) show similar efficacy and mechanism to MSCs in the treatment of osteoarthritis. This article provides a comprehensive overview of the role of macrophages in the development and progression of osteoarthritis, the impact of MSCs on macrophages, as well as the role and mechanism of macrophages in the treatment of osteoarthritis with MSCs, so as to lay a theoretical foundation for the clinical applications of MSCs in the treatment of osteoarthritis.