AbstractCOVID‐19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID‐19 patients, we found extensive accumulation of the tryptophan degradation products 3‐hydroxy‐anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan‐catabolizing indoleamine 2,3‐dioxygenase (IDO)‐1, but rather to that of its isoform IDO‐2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO‐2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl‐hydrocarbon receptor/IDO‐2 axis as a positive feedback loop, potentially leading to severe COVID‐19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.