With the use of first-principles simulations, low barrier CO oxidation reactions are predicted to occur via a Langmuir-Hinshelwood or an Eley-Rideal mechanism, on two-dimensional gold nanocluster islands adsorbed on two-layer MgO films that are supported on Mo(100). Underlying the emergent catalytic activity, predicted to occur even in the absence of oxygen vacancy F-center defects, is the excess electronic charge at the gold cluster/magnesia interface originating from the penetration of metal states through the thin magnesia film. This excess charge stabilizes the planar structure of the gold cluster and activates the oxygen molecules adsorbed at the interfacial periphery of the gold islands.