Co-based nanoalloys show potential applications as nanocatalysts for the oxygen reduction reaction (ORR), but improving their activity is still a great challenge. In this paper, a strategy is proposed to design efficient Co-M (M= Au, Ag, Pd, Pt, Ir, and Rh) nanoalloys as ORR catalysts by using density functional theory (DFT) calculations. Through the Sabatier analysis, the overpotential as a function of ΔGOH* is identified as a quantitative descriptor for analyzing the effect of dopants and atomic structures on the activity of the Co-based nanoalloys. By adopting the suitable dopants and atomic structures, ΔGOH* accompanied by overpotential could be adjusted to the optimal range to enhance the activity of the Co-based nanoalloys. With this strategy, the core–shell structured Ag42Co13 nanoalloy is predicted to have the highest catalytic activity for ORR among these Cobased nanoalloys. To give a deeper insight into the properties of Ag-Co nanoalloys, the structure, thermal stability, and reaction mechanism of Ag-Co nanoalloys with different compositions are also studied by using molecular simulations and DFT calculations. It is found that core–shell Ag42Co13 exhibits the highest structural and thermal stability among these Ag-Co nanoalloys. In addition, the core–shell Ag42Co13 shows the lowest ORR reaction energy barriers among these Ag-Co nanoalloys. It is expected that this kind of strategy could provide a viable way to design highly efficient heterogeneous catalysts in extensive applications. [ABSTRACT FROM AUTHOR]