Electronic interaction between metal nanoparticles and irreducible supports is an important aspect of heterogeneous catalysis due to its capability of controlling the associated catalytic performance. We elucidate the relationship between metal−support electronic interactions and catalytic activity on size-selected singe layered platinum plates Pt n (n = 10, 20, 30, and 45) supported on a Si (111)-7 × 7 reconstructed surface (Si-RS). Our first-principles density functional theory study shows that CO oxidation catalysis over Pt supported on the nonreducible Si-RS is affected by variations in charge transfer, cluster size, and electronic interactions between clusters and support. CO adsorbs on Pt n adsorption sites in two distinct ranges of adsorption energies, which explains the experimentally observed two different desorption temperatures of CO. Pt 30 /Si-RS is more active than other Pt n /Si-RS under the same conditions, showing markedly enhanced catalytic activity in terms of high turnover frequency of CO 2 production. This superior activity originates from the optimum CO and O 2 adsorption on Pt 30 arising from the position of the d-band center being midway between their π orbitals. Experimental observations convey that the TOFs of CO 2 production on Pt 30(45) /Si-RS are very high, and these are tolerant to CO poisoning between 450 and 550 K. DFT computations of TOF on Pt 30(45) /Si-RS for CO 2 validate the experimentally observed trends at 350, 450, and 550 K and exhibit that the CO oxidation activity exceeds that of the conventional catalysts between 450 and 550 K. Our results depict the importance of size control and electronic structure tailoring while designing Pt-based catalysts and will motivate the effective utilization of rare elements on irreducible substrates.