Electrocatalysts with high activity and long-term stability for the hydrogen oxidation reaction (HOR) under alkaline conditions is still a major challenge for anion exchange membrane fuel cells (AEMFCs). Herein, a heterostructured Ir@Pd electrocatalyst with ultrasmall Ir nanoclusters (NCs) epitaxially confined on Pd nanosheets (NSs) for catalyzing the sluggish alkaline HOR is reported. Apparent charge redistribution occurs across the heterointerface, and both experimental and theoretical results suggest that the electrons transfer from Pd to Ir, which consequently greatly weakens the hydrogen binding on Pd. More interestingly, the interfacial epitaxy results in the formation of Ir/IrO2 Janus nanostructures, where the partially oxidized Ir species away from the interface further optimize the hydroxyl adsorption behavior. The unique Ir@Pd heterostructure eventually shows an optimal balance between hydrogen and hydroxyl adsorption, and hence exhibits impressive HOR activity with an exchange current density of up to 7.18 mA cm–2 in 0.1 m KOH solution. In addition, the Ir@Pd electrocatalyst exhibits negligible activity degradation owing to the confinement effect of the unique epitaxial interface.