AbstractHerein we present a theoretical study of the reaction of singlet oxygen with histidine performed both in the gas phase and in aqueous solution. The potential energy surface of the reactive system was explored at the B3LYP/cc‐pVTZ level of theory and the electronic energies were refined by means of single‐point CCSD(T)/cc‐pVTZ(‐f) calculations. Solvent effects were taken into account by using a solvent continuum model (COSMO) and by adding explicit water molecules. The results show that the first step in the reaction mechanism corresponds to a nearly symmetric Diels–Alder addition of the singlet oxygen molecule to the imidazole ring to yield an endoperoxide, in agreement with experimental evidence. The intermediate formed can evolve along two different reaction paths leading to two isomeric hydroperoxides and, eventually, to open‐chain or internally cyclised oxidised products. Water plays a significant role in stabilising the reaction structures by solvation and by acting as a b