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Developing highly active Pd-based nanocatalysts with a well-organized structure is desired for direct alcohol fuel cell commercialization. In this study, room temperature seed mediated growth strategy has been successfully developed to prepare ternary Pd@Cdx-Agy core-shell as advanced novel non-Pt anode nanocatalysts for ethanol oxidation reaction EOR in alkaline electrolyte. The introduction of oxophilic Cd and Ag metals into Pd nanocatalysts can reduce the adsorption energy of OHads on the Pd@Cdx-Agy nanocatalysts and inhibit the COads on the Pd surface. Morphological characterization demonstrates that the as-synthesized Pd@Cdx-Agy nanocatalysts are well-organized core-shell nanostructure with Pd NPs as the core and Cd-Ag alloy as the shell. Moreover, electrochemical results indicate that the Pd@Cd1-Ag1 core-shell catalyst exhibit a remarkable electrochemical activity ( 2995.76 mA mg Pd − 1 ), excellent CO tolerance and long-term durability compared to those of Pd@Cd ( 1285.9 mA mg Pd − 1 ), Pd@Ag ( 2423.52 mA mg Pd − 1 ) and commercial Pd/C (JM) ( 477.4 mA mg Pd − 1 ) nanocatalysts. The excellent catalytic activity and stability of Pd@Cd1-Ag1 nanocatalyst can be associated to their huge electrochemical active surface area, positive influence of Cd-Ag NPs on Pd NPs and the unique well-organized core-shell nanostructure. These results suggested that the as-synthesized Pd@Cdx-Agy core-shell could serve as advanced catalysts towards alkaline DEFCs.