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We address the question of the nature of Au NP activation and through a combination of experimental and theoretical techniques. In‐situ XPS measurements of Au/TiO₂ during CO oxidation show high catalytic activity can be associated with the formation of an ionic Au species. DFT calculations performed on Au/TiO₂ show that the formation of such ionic Au is due to a strong metal‐support interaction between Au and reduced and defective TiO₂. TEM supports these findings, indicating the formation of an overlayer of transition metal oxide support on Au NPs after CO oxidation. These results suggest TiO₂ lattice oxygen is involved directly in CO oxidation, which was confirmed with labeled ¹⁸O₂ experiments.