Developing a highly efficient catalyst with lower Pt content for the oxygen reduction reaction (ORR) is highly sought for fuel cell applications. The potential applicability of a cuboctahedral core-shell (Ti19@Pt60) nanocluster (NC) toward ORR activity has been investigated and compared with that of a pure Pt NC (Pt79). The energetic stability, thermal stability, and dissolution limit of Ti19@Pt60 NCs has been investigated for their possible synthesis and practical usages. Thermodynamic and kinetic parameters are explored to find out the most favored ORR pathway and product selectivity on the Ti19@Pt60 NC. Rate-determining steps (∗O2 activation and∗OH formation) are highly improved over the Ti19@Pt60 NC with respect to the cuboctahedral Pt NC (Pt79), pure metal (Pt, Pd, and Ag), and alloy (Pt3M; M = Ni, Co, Ti) based catalysts. Our detailed investigation reveals that the∗O2-induced structural changes favor direct∗O2 dissociation on the Ti19@Pt60 NC surface. Further, we find that a dual mechanism (ligand effect and charge transfer) plays an important role to improve the ORR activity. The results obtained in this study provide fundamental insight into the role of a core-shell NC toward ORR activity. © 2016 American Chemical Society.