Nickel (Ni) is a promising electrocatalyst for alkaline hydrogen oxidation reaction (HOR). However, the strong hydrogen binding at Ni site (Ni–H) limits its electrocatalytic HOR activity. Herein, ruthenium (Ru) is introduced to regulate the surface electronic structure of Ni and optimize the Ni–H. Simultaneously, constructing the interfacial-oxygen (O) configuration endows Ni with suitable oxophilic components to optimize the adsorption energy for surface hydroxyl species (OH*). The density functional theory (DFT) simulation and characterization results confirm that electron transfer from Ni to Ru causes the d-band center of Ni to shift down, weakening the hydrogen binding energy (HBE) and hydroxyl binding energy (OHBE), which synergistically contributes the enhanced HOR performance for the optimal O-RuNi@C-400 with a diffusion-limiting current density of 2.87 mA cm–2 and mass activity of 601 mA mg–1PGM at an overpotential of 50 mV, which is ∼1.20 and 7.90 times higher than that of Pt/C, respectively. Besides, because of the protective shell of oxophilic Ni–O–C interface to reduce the affinity with CO, O-RuNi@C-400 exhibits better CO tolerance (1000 ppm) than that of commercial Pt/C in alkaline media, making it a promising HOR electrocatalyst for hydrogen fuel cells.