Despite significant research efforts, designing bimetallic catalysts rationally remains a challenging task. Herein, we combine the strengths of high-throughput experiments and DFT calculations synergistically to design new core–shell bimetallic catalysts. The total oxidation of propane is used as a probe, proof-of-concept reaction. The methodology is successful in designing three bimetallic catalysts. Of these catalysts, AgPd is cheaper, more active than the existing most active single-metal catalyst (Pt), and stable under the reaction conditions. Extended X-ray absorption fine structure characterization confirms the formation of a bimetallic alloy. This study provides a path forward for designing bimetallic catalysts rationally for vapor phase metal-catalyzed reactions.