Hydroxide exchange membrane fuel cell (HEMFC) is a potentially cost-effective energy conversion technology. However, current state-of-the-art HEMFCs require a high loading of platinum-group-metal (PGM) catalysts, especially for the hydrogen oxidation reaction. Here we develop a porous nitrogen-doped carbon-suppported PtRu hydrogen oxidation reaction catalyst (PtRu/pN-C) that has a high intrinsic and mass activity in alkaline condition. Spectroscopic and microscopic data indicate the presence of Pt single atoms in addition to PtRu nanoparticles on pN-C. Mechanistic study suggests Ru modulates the electronic structure of Pt for an optimized hydrogen binding energy, while Pt single atoms on pN-C optimize the interfacial water structure. These synergetic interactions are responsible for the high catalytic activity of this catalyst. An HEMFC with a low loading of this catalyst and a commercial Fe–N–C oxygen reduction reaction catalyst achieves a high PGM utilization rate. The current density at 0.65 V of this HEMFC reaches 1.5 A cm⁻², exceeding the US Department of Energy 2022 target (1 A cm⁻²) by 50%.