Density functional theory was used to study the CO oxidation catalytic activity of CeO2-supported Au nanoparticles (NPs). Experimental observations on CeO2 show that the surface of CeO2 is enriched with oxygen vacancies. We compare CO oxidation by a Au-13 NP supported on stoichiometric CeO2 (Au-13@CeO2-STO) and partially reduced CeO2 with three vacancies (Au-13@CeO2-3VAC). The structure of the Au-13 NP was chosen to minimize structural rearrangement during CO oxidation. We suggest three CO oxidation mechanisms by Au-13@CeO2: CO oxidation by coadsorbed O-2, CO oxidation by a lattice oxygen in CeO2, and CO oxidation by O-2 bound to a Au-Ce3+ anchoring site. Oxygen vacancies are shown to open a new CO oxidation pathway by O-2 bound to a Au-Ce3+ anchoring site. Our results provide a design strategy for CO oxidation on supported Au catalysts. We suggest lowering the vacancy formation energy of the supporting oxide, and using an easily reducible oxide to increase the concentration of reduced metal ions, which act as anchoring sites for O-2 molecules.