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8‐Oxoguanosine is the most common oxidatively generated base damage and pairs with complementary cytidine within duplex DNA. The 8‐oxoguanosine−cytidine lesion, if not recognized and removed, not only leads to G‐to‐T transversion mutations but renders the base pair being more vulnerable to the ionizing radiation and singlet oxygen (¹O₂) damage. Herein, reaction dynamics of a prototype Watson−Crick base pair [9MOG ⋅ 1MC]⋅⁺, consisting of 9‐methyl‐8‐oxoguanine radical cation (9MOG⋅⁺) and 1‐methylcystosine (1MC), was examined using mass spectrometry coupled with electrospray ionization. We first detected base‐pair dissociation in collisions with the Xe gas, which provided insight into intra‐base pair proton transfer of 9MOG⋅⁺ ⋅ 1MC[9MOG − H_N1]⋅ ⋅ [1MC+H_N3′]⁺and subsequent non‐statistical base‐pair separation. We then measured the reaction of [9MOG ⋅ 1MC]⋅⁺with¹O₂, revealing the two most probable pathways, C5‐O₂addition and H_N7‐abstraction at 9MOG. Reactions were entangled with the two forms of 9MOG radicals and base‐pair structures as well as multi‐configurations between open‐shell radicals and¹O₂(that has a mixed singlet/triplet character). These were disentangled by utilizing approximately spin‐projected density functional theory, coupled‐cluster theory and multi‐referential electronic structure modeling. The work delineated base‐pair structural context effects and determined relative reactivity toward¹O₂as [9MOG − H]⋅>9MOG⋅⁺>[9MOG − H_N1]⋅ ⋅ [1MC+H_N3′]⁺≥9MOG⋅⁺ ⋅ 1MC.

8‐Oxo‐2′‐deoxyguanosine (OG) is the most common DNA lesion. Notably, OG becomes more susceptible to oxidative damage than the undamaged nucleoside, forming mutagenic products in vivo. Herein the reactions of singlet O₂with the radical cations of 8‐oxo‐2′‐deoxyguanosine (OG^.+) and 9‐methyl‐8‐oxoguanine (9MOG^.+) were investigated using ion‐molecule scattering mass spectrometry, from which barrierless, exothermic O₂‐addition products were detected for both reaction systems. Corroborated by static reaction potential energy surface constructed using multi‐reference CASPT2 theory and molecular dynamics simulated in the presence of the reactants′ kinetic and internal energies, the C5‐terminal O₂‐addition was pinpointed as the most probable reaction pathway. By elucidating the reaction mechanism, kinetics and dynamics, and reaction products and energetics, this work constitutes the first report unraveling the synergetic damage of OG by ionizing radiation and singlet O₂.