Significance Besides being a protein building block, the essential amino acid tryptophan is a neurotransmitter precursor and a potent immunomodulator. Therefore, its systemic concentration needs to be constant in spite of irregular dietary supply. How this is achieved is unclear. Dietary tryptophan is degraded in the liver by tryptophan 2,3-dioxygenase (TDO). We report that tryptophan itself regulates TDO stability: Abundant tryptophan binds to noncatalytic exosites and stabilizes active tetrameric TDO. Hence, tryptophan is rapidly degraded and tryptophanemia contained. When tryptophan is scarce, it detaches from exosites, inducing tetramer dissociation and unmasking a degron triggering TDO polyubiquitination and proteasome-mediated degradation. Tryptophan catabolism is interrupted and blood level maintained. Matching catabolism to dietary supply, this mechanism ensures rapid and tight control of tryptophanemia.