Fibrosis can occur in all major organs with relentless progress, ultimately leading to organ failure and potentially death. Unfortunately, current clinical treatments cannot prevent or reverse tissue fibrosis. Thus, new and effective antifibrotic therapeutics are urgently needed. In recent years, a growing body of research shows that macrophages are involved in fibrosis. Macrophages are highly heterogeneous, polarizing into different phenotypes. Some studies have found that regulating macrophage polarization can inhibit the development of inflammation and cancer. However, the exact mechanism of macrophage polarization in different tissue fibrosis has not been fully elucidated. This review will discuss the major signaling pathways relevant to macrophage-driven fibrosis and profibrotic macrophage polarization, the role of macrophage polarization in fibrosis of lung, kidney, liver, skin, and heart, potential therapeutics targets, and investigational drugs currently in development, and hopefully, provide a useful review for the future treatment of fibrosis.