Alpha-ketoglutarate (AKG) is a crucial intermediate of the Krebs cycle and plays a critical role in multiple metabolic processes in animals and humans. Of note, AKG contributes to the oxidation of nutrients (i.e., amino acids, glucose, fatty acids) and then provides energy for cell processes. As a precursor of glutamate and glutamine, AKG acts as an antioxidant agent as it directly reacts with hydrogen peroxide with formation of succinate, water, and carbon dioxide; meanwhile, it discharges plenty of ATP by oxidative decarboxylation. Recent studies also show that AKG has alleviative effect on oxidative stress as a source of energy and an antioxidant in mammalian cells. In this review, we highlight recent advances in the antioxidative function of AKG and its applications in animals and humans.