Despite recent efforts on replacing a noble Pt to less expensive catalysts (such as Pt-Ni and Pt-Co alloys) for improving oxygen reduction reaction (ORR) for PEMFC (polymer electrolyte membrane fuel cell) application, the performance and stability of a noble Pt catalyst still remains superior. In the present study, we have proposed the systematic procedure for designing the Ir3M (M = 3d, 4 d, 5 d transition metal) nanoalloy as Pt alternatives with enhanced ORR activity and stability using density functional theory (DFT) and experimental methods. First, we computationally optimized the surface occupied/unoccupied d states and lattice distance of the thermodynamically-stable Ir3M nanoalloy in order to achieve the wanted oxygen affinity for promoting ORR. In the next screening process, the nanoalloy prone to the segregation of inside M atom toward the surface layer was excluded, leading ultimately to the potential candidates such as the pure Ir monolayer on the top of Ir3Cr, Ir3V, Ir3Re, and Ir3Tc alloy cores. Finally, a pure Ir monolayer on the top of Ir3Cr core (which was expected to show the most enhanced ORR activity among the computationally-screened candidates) was experimentally prepared via physical vapor deposition method (PVD) and electrochemically evaluated for confirming our DFT prediction. Our synthesis successfully produced a 3 nm Ir-covered (so-called Ir skinlayer) Ir3Cr nanoparticle (Ir/Ir3Cr), which displayed the surface lattice contraction by 1.03% compared to the pure Ir case. The specific activity (at 0.7 V vs RHE) of a Ir/Ir3Cr catalyst with the very high durability (showing only 0.05% decrease from the initial activity after 3000 potential cycles) was 12.3 times higher than a Ir catalyst. The detail mechanism on the enhanced activity in Ir-M alloy was also examined. The design principle of alloy catalysts used in this study can be further extended to the screening of catalytic materials for the application to the next-level electrochemical reaction.