Abstract Ruthenium has emerged as a promising alternative to iridium in water‐splitting anodes. However, it becomes overoxidized and dissolves at industry‐relevant working conditions. To enhance the activity and stability of electrocatalysts for oxygen evolution reaction, an isostructural rutile MnRu oxide with low Ru concentration (Mn 0.75 Ru 0.25 O 2 ) is synthesized and an asymmetric Mn‐O‐Ru dual‐site active center is developed. It exhibits 154 mV overpotential at 10 mA cm −2 and can operate stably at 200 mA cm −2 for 670 h with a degradation rate of 29 uV/h −1 . A proton exchange membrane water electrolyzer achieves stable operation at 1 A cm −2 for 700 h with a degradation rate of 53 uV h −1 . Structural analysis and isotopic labeling correlate the asymmetric nature of the Mn‐O‐Ru dual‐site active center, which facilitates the oxygen evolution reaction along the radical coupling pathway, with the stabilization of the cations and the lattice oxygen in isostructural rutile Mn 0.75 Ru 0.25 O 2 .