Designing Pt-based electrocatalysts with high catalytic activity and CO tolerance is challenging but extremely desirable for alkaline hydrogen oxidation reaction. Herein we report the design of a series of single-atom lanthanide (La, Ce, Pr, Nd, and Lu)-embedded ultrasmall Pt nanoclusters for efficient alkaline hydrogen electro-oxidation catalysis based on vapor filling and spatially confined reduction/growth of metal species. Mechanism studies reveal that oxophilic single-atom lanthanide species in Pt nanoclusters can serve as the Lewis acid site for selective OH-adsorption and regulate the binding strength of intermediates on Pt sites, which promotes the kinetics of hydrogen oxidation and CO oxidation by accelerating the combination of OH−and *H/*CO in kinetics and thermodynamics, endowing the electrocatalyst with up to 14.3-times higher mass activity than commercial Pt/C and enhanced CO tolerance. This work may shed light on the design of metal nanocluster-based electrocatalysts for energy conversion.