A high-entropy single-atom catalyst (HESAC) composed of Fe, Co, Ni, and Ru metals on nitrogen-doped graphene (FeCoNiRu-HESAC) was designed for the oxygen reduction reaction (ORR) in both acidic and alkaline conditions. This HESAC has 5.2 times higher entropy than conventional single-atom catalysts (SACs). The Fe active sites in FeCoNiRu-HESAC exhibit a low ORR overpotential of 0.44 V, attributed to weakened adsorption of OH intermediates. Density functional theory (DFT) calculations predicted the catalytic activity, which was experimentally verified. FeCoNiRu-HESAC showed overpotentials of 0.41 and 0.37 V with Tafel slopes of 101 and 210 mV dec⁻¹ at 1 mA cm⁻² in acidic and alkaline electrolytes, comparable to Pt/C. The catalyst was applied in Zinc–air batteries, achieving an open circuit potential of 1.39 V and power density of 0.16 W cm⁻². The study provides a DFT-guided strategy for designing HESACs with enhanced ORR performance, potentially replacing expensive Pt catalysts. The FeCoNiRu-HESAC was synthesized using a two-step pyrolysis method, and its structure was confirmed via XPS, XAS, and STEM. The catalyst demonstrated high stability and electrochemical activity, with no significant degradation after 1000 ORR cycles. The results highlight the potential of HESACs for efficient and sustainable energy conversion and storage applications.A high-entropy single-atom catalyst (HESAC) composed of Fe, Co, Ni, and Ru metals on nitrogen-doped graphene (FeCoNiRu-HESAC) was designed for the oxygen reduction reaction (ORR) in both acidic and alkaline conditions. This HESAC has 5.2 times higher entropy than conventional single-atom catalysts (SACs). The Fe active sites in FeCoNiRu-HESAC exhibit a low ORR overpotential of 0.44 V, attributed to weakened adsorption of OH intermediates. Density functional theory (DFT) calculations predicted the catalytic activity, which was experimentally verified. FeCoNiRu-HESAC showed overpotentials of 0.41 and 0.37 V with Tafel slopes of 101 and 210 mV dec⁻¹ at 1 mA cm⁻² in acidic and alkaline electrolytes, comparable to Pt/C. The catalyst was applied in Zinc–air batteries, achieving an open circuit potential of 1.39 V and power density of 0.16 W cm⁻². The study provides a DFT-guided strategy for designing HESACs with enhanced ORR performance, potentially replacing expensive Pt catalysts. The FeCoNiRu-HESAC was synthesized using a two-step pyrolysis method, and its structure was confirmed via XPS, XAS, and STEM. The catalyst demonstrated high stability and electrochemical activity, with no significant degradation after 1000 ORR cycles. The results highlight the potential of HESACs for efficient and sustainable energy conversion and storage applications.