Emerging as a new frontier in heterogeneous catalysis, single-atom site catalysts (SSCs) have sparked enormous attention and bring about new opportunities to oxygen reduction electrocatalysis. Despite considerable progress achieved recently, most of the reported SSCs suffer from either insufficient activity or unsatisfactory stability, which severely retards their practical application. Here, we demonstrate a novel Ru-SSC with appropriate,mod., adsorption free energy of OH* (Delta G(OH)*) to confer excellent activity and low Fenton reactivity to maintain long-term stability. The as-developed Ru-SSC exhibits encouraging oxygen reduction reaction turnover frequency of 4.99 e(-) s(-1) sites(-1), far exceeding the state-of-the-art Fe-SSC counterpart (0.816 e(-) s(-1) sites(-1)), as a result of Ru energy level regulation via spontaneous OH binding. Furthermore, Ru-SSC exhibits greatly suppressed Fenton reactivity, with restrained generation of reactive oxygen species directly observed, thus endowing the Ru-SSC with much more superior stability (only 17 mV negative shift after 20 000 cycles) than the Fe-SSC counterpart (31 mV). The practical application of Ru-SSC is further validated by its excellent activity and stability in a real fuel cell device.