The spontaneous formation and long-term surface stabilization of superoxide radicals are observed on specific TiO2 hybrid materials in which titanium is coordinated to an organic ligand. Here the rationale for this uncommon phenomenon is investigated by a synergistic theoretical and experimental approach involving density functional theory (DFT) calculations and spectroscopic techniques. Stoichiometric and reduced anatase (101) surfaces modified with acetylacetone, dibenzoylmethane, and catechol are comparatively examined. These results reveal that the interaction between organic ligands and adsorbed O2 molecules improves when O vacancies are present on the external layer of the surface, promoting O2 reduction. The electronic features of the ligand play a pivotal role for both an effective electronic interaction with the surface and the stabilization of the generated reactive oxygen species. These results agree with experimental data showing that sol–gel-derived Ti-diketonate hybrid oxides spontaneously produce very persistent superoxide radicals under ambient conditions, thus holding a high intrinsic oxidative activity.