Despite tremendous importance in catalysis, the design and improvement of the oxide- metal interface has been hampered by the limited understanding on the nature of interfacial sites, as well as the oxide-metal interaction (OMI). Through the construction of well-defined Cu2O-Pt, Cu2O-Ag, Cu2O-Au interfaces, we found that Cu2O Nanostructures (NSs) on Pt exhibit much lower thermal stability than on Ag and Au, although they show the same surface and edge structures, as identified by element-specific scanning tunneling microscopy (ES-STM) images. The activities of the Cu2O-Pt and Cu2O-Au interfaces for CO oxidation were further compared at the atomic scale and showed in general that the interface with Cu2O NSs could annihilate the CO-poisoning problem suffered by Pt group metals and enhance the interaction with O2, which is a limiting step for CO oxidation catalysis on group IB metals. While both interfaces could react with CO at room temperature, the OMI was found to determine the reactivity of supported Cu2O NSs by 1) tuning the activity of interfacial oxygen atoms and 2) stabilizing oxygen vacancies or vice versa, the dissociated oxygen atoms at the interface. Our study provides new insight for OMI and for the development of Cu-based catalysts for low temperature oxidation reactions.