Silver nanoparticles (NPs) developed on a copper substrate, Ag NPs/Cu, are synthesized by a novel and facile galvanic replacement method performed in Ethaline deep eutectic solvent (DES). It reveals that the Ag NPs could be well dispersed on the Cu support via an in-situ electrochemical oxidation-reduction (ECO-ECR) activation process, which deliver significantly enhanced activity and stability for the oxygen reduction reaction (ORR) in alkaline media. The in-situ redox tuning triggers a reversible phase transformation of the formed initially Ag NPs, Ag <-> Ag2O, with surface reconstruction and gives rise to a strong metal-support interaction with tailored atomic/electronic structures, resulting in enhanced ORR activity. Impressively, the introduction of Ni-II ions can regulate the galvanic replacement kinetics by mediating the diffusion of Ag-I ions and subsequent growth of Ag on the Cu surface in Ethaline, leading to the formation of uniformly distributed Ag NPs. Coupled with redox activation, the optimal Ag-Ni-1 NPs/Cu_ECO-ECR exhibits ORR activity similar to that of the commercial state-of-the-art Pt/C catalyst, and better long-term durability (95% activity retention after 30,000 s), cyclic stability performance, and anti-poisoning capacity for methanol (96% after 3300 s), suggesting it a promising ORR electrocatalyst for practical application. (C) 2020 Elsevier Inc. All rights reserved.