Macrophages are multifunctional immune cells whose functions depend on polarizable phenotypes and the microenvironment. Macrophages have two phenotypes, including the M1 proinflammatory phenotype and the M2 anti-inflammatory phenotype, which play important roles in many inflammatory responses and diseases. α-Ketoglutarate is a key metabolite of the TCA cycle and can regulate the phenotype of macrophage polarization to exert anti-inflammatory effects in many inflammation-related diseases. In this review, we primarily elucidate the metabolism, regulatory mechanism, and perspectives of α-ketoglutarate on macrophages. The regulation of macrophage polarization by α-ketoglutarate may provide a promising target for the prevention and therapy of inflammatory diseases and is beneficial to animal health.