Inspired by the single-atom catalysts (SACs) concept, we rationally design a series of Pt single atom catalysts embedded in different transition metal nanoclusters through first-principles calculations. In these so-called “crown-jewel” (CJ) structures, Pt atoms (jewels) occupy the vertex sites of the metal nanocluster (crown) surface. We investigated the thermal stability and oxygen reduction reaction (ORR) catalytic activity of these catalysts. The results reveal that CJ-structured PtCu nanoclusters are stable and possess a comparable or even better ORR activity compared to Pt catalyst, making it a promising candidate for low-cost ORR catalysts. The effect of cluster size on the adsorption strength of ORR intermediates and catalytic property has also been studied. Furthermore, the overall ORR catalytic activity trend of these SACs is explained based on analysis of their electronic properties. A descriptor Ψ was established to provide further insight into the correlation between the electronic structure and catalytic activity, which provides a design strategy for new ORR catalysts. More importantly, we reveal that this electronic descriptor can be extended to predict other CJ-structured nanoclusters.