Macrophages are one of the crucial mediators of the immune response in different physiological and pathological conditions. These cells have critical functions in the inflammation mechanisms that are involved in the inhibition or progression of a wide range of diseases including cancer, autoimmune diseases, etc. It has been shown that macrophages are generally divided into two subtypes, M1 and M2, which are distinguished on the basis of their different gene expression patterns and phenotype. M1 macrophages are known as pro-inflammatory cells and are involved in inflammatory mechanisms, whereas M2 macrophages are known as anti-inflammatory cells that are involved in the inhibition of the inflammatory pathways. M2 macrophages help in tissue healing via producing anti-inflammatory cytokines. Increasing evidence indicated that the appearance of different macrophage subtypes is associated with the fate of diseases (progression versus suppression). Hence, polarization of macrophages can be introduced as an important venue in finding, designing and developing novel therapeutic approaches. Albeit, there are different pharmacological agents that are used for the treatment of various disorders, it has been shown that several natural compounds have the potential to regulate M1 to M2 macrophage polarization and vice versa. Herein, for the first time, we summarized new insights into the pharmacological effects of natural compounds on macrophage polarization.