Developing efficient and stable oxygen evolution reaction (OER) electrocatalysts is essential for the production of hydrogen from water electrolysis. Here, we successfully synthesized a high-entropy ruthenium-based oxide (RuMnFeCoNiO-HEO) with rich grain boundaries using a fast and nonequilibrium molten salt method. The RuMnFeCoNiO-HEO with significantly reduced ruthenium dosage could exhibit much higher OER performance with a low overpotential of 190 mV at 10 mA/cm2 and long-term durability of 100-h continuous operation under 100 mA/cm2 in alkaline solution. The mass activity and turnover frequency of RuFeCoNiMn-HEO are significantly enhanced by nearly 1 order of magnitude compared to those of commercial RuO2. Microstructural characterizations reveal that the incorporation of four extra 3d transition metals into ruthenium oxides results in the formation of Ru-based high-entropy materials with a rich grain boundary structure and unsaturated coordination Ru active centers, which optimize both the electrocatalytic activity and electrochemical durability of RuMnFeCoNiO-HEO during the OER process.