Reactivity at metal-oxide interfaces is of fundamental importance in heterogeneous catalysis. Herein, we report a thorough surface-science study on the growth and chemical activity of ultrathin ZnO films on Ag(111) by grazing-emission X-ray photoelectron spectroscopy and temperature-dependent infrared reflection–absorption spectroscopy using CO as a probe molecule. Compared to bilayer ZnO on Cu [Schott, V.; Angew. Chem. Int. Ed. 2013, 52, 11925–11929], we find a much decreased CO binding energy of 0.24 eV for bilayer ZnO on Ag. Furthermore, the anomalous, substantial red-shift of the CO stretch frequency with respect to the gas phase value identified for ZnO/Cu is absent in the ZnO/Ag system, where we instead report a slightly blue-shifted frequency at 2146 cm–1 for isolated CO molecules. In order to interpret these differences of ZnO thin layer supported on these two coinage metals, we carried out a thorough theoretical analysis using density functional theory calculations employing van der Waals-corrected generalized-gradient-approximation (GGA)-type and hybrid functionals. We show that bilayer ZnO forms a flat graphitic-like structure on Ag in contrast to the previously reported strongly corrugated ZnO film formed on Cu. While our results show that GGA-type functionals cannot in general be applied uncritically for CO adsorption on ZnO, we explicitly validate our results for the ZnO/Ag system by comparison to hybrid functional calculations for selected model systems.