The face-centered cubic (fcc) Ru exhibits great potential for the alkaline hydrogen oxidation reaction (HOR), while achieving high HOR activity and CO tolerance poses a formidable challenge for Ru catalysts in practical fuel cells, particularly when using CO-contaminated H2, such as gray and blue hydrogen. Here, we propose a compositional diversification strategy to create 14 types of fcc Ru-based alloys, in which adjustable compositions can tune the nanostructure while offsetting the limitations of single Ru. Among them, quinary RuInPtNiCu nanocrystals (NCs) exhibit an outstanding HOR activity of 5.36 A mgPGM-1, which is 15.9 and 2.9 times higher than those of commercial Pt/C (0.338 A mgPGM-1) and single Ru NCs (1.88 A mgPGM-1), respectively. More importantly, the RuInPtNiCu-based membrane electrode assembly (MEA) achieves a high peak power density of 1.72 W cm-2 and a remarkable mass activity of 19.0 A mgPGM-1@0.65 V in H2-O2, and the RuInPtNiCu-based MEA can be run stably at 0.6 A cm-2 for over 100 h. Moreover, the RuInPtNiCu retains 94.6% of the HOR current after exposure to H2 containing 1000 ppm CO for 8000 s in a rotating disk electrode and retains 92.5% of cell voltage after a CO-toxicity stability test in fuel cells, underscoring its exceptional CO tolerance. Mechanism and computation studies corroborate that the optimized electronic structure and atomic configuration of RuInPtNiCu weaken the adsorption of surface species (*H, *OH, and CO) and alter the CO adsorption mode on active sites, thus leading to enhanced HOR performance and CO tolerance.