With the increasingly stringent emission regulations and higher fuel economy standards, thedevelopment of low temperature oxidation catalyst becomes vital. Guided by a previously developed computational screening framework, we have discovered a PdCu/SiO2 alloy catalyst with the ability to fully oxidize CO without NO inhibition below 150˚C. Extensive characterization studies by TEM and XAS reveal the active structure to be a metallic Cu-rich surface on top of Pd-core nanoclusters. The unique inhibition-free oxidation activity makes PdCu/SiO2 a better CO oxidation catalyst than a reference PtPd/SiO2 sample when NO co-exists in the feed. Conversely, NO oxidation over the PdCu alloy catalyst is also free of CO inhibition, but the conversion level remains insufficient to make a good DOC. A flow reactor loaded sequentially with PdCu upstream and PtPd downstream to form a dual-bed catalyst configuration synergistically combines the superior activity of PdCu for CO oxidation and the high efficiency of PtPd for NO oxidation. In this arrangement, CO oxidizes upstream over the inhibition-resistant PdCu catalyst, which in turn prevents CO from inhibiting NO oxidation in the downstream PtPd section. The CO oxidation performance of the PdCu alloy was found to be robust even with up to 2% of water in the feed. The reported PdCu/SiO2 catalyst was inspired by computational work aiming to minimize the mutual inhibition between NO and CO oxidation. Remarkably, the theoretical predictions were confirmed, but experiments with added propylene to simulate the presence of unburned hydrocarbons in the exhaust gas demonstrate the need for further research. The new catalyst formulation has not been optimized to minimize inhibition by propylene, but a modified screening framework can potentially address this issue. Overall, the PdCu+PtPd dual-bed catalyst configuration solves the 150°C challenge for CO oxidation at reduced cost. If combined with a PNA or HCT upstream of the DOC, it carries great potential for practical applications and enabling the widespread adoption of fuel-efficient, low temperature combustion diesel engines.