The paper presents the design and synthesis of a high-entropy single-atom catalyst (HESAC) for the oxygen reduction reaction (ORR) in acidic and alkaline conditions. The HESAC, composed of Fe, Co, Ni, and Ru, exhibits 5.2 times higher entropy compared to single-atom catalysts (SACs). The Fe active sites with an intermetallic distance of 6.1 Å show a low ORR overpotential of 0.44 V, attributed to the weakening of OH intermediate adsorption. Density functional theory (DFT) calculations and machine learning (ML) analysis predict the optimal structure and performance of the HESAC. The synthesized FeCoNiRu-HESAC is confirmed by X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), and scanning transmission electron microscopy (STEM). Experimental results show that the HESAC has overpotentials of 0.41 and 0.37 V in acidic and alkaline electrolytes, respectively, with Tafel slopes of 101 and 210 mV dec\(^{-1}\) at a current density of 1 mA cm\(^{-2}\). These values are comparable to those of Pt/C. The HESAC is also tested in a Zinc-air battery, achieving an open circuit potential of 1.39 V and a power density of 0.16 W cm\(^{-2}\). The study demonstrates a rational design strategy for HESACs that can replace high-cost Pt catalysts in ORR and beyond.The paper presents the design and synthesis of a high-entropy single-atom catalyst (HESAC) for the oxygen reduction reaction (ORR) in acidic and alkaline conditions. The HESAC, composed of Fe, Co, Ni, and Ru, exhibits 5.2 times higher entropy compared to single-atom catalysts (SACs). The Fe active sites with an intermetallic distance of 6.1 Å show a low ORR overpotential of 0.44 V, attributed to the weakening of OH intermediate adsorption. Density functional theory (DFT) calculations and machine learning (ML) analysis predict the optimal structure and performance of the HESAC. The synthesized FeCoNiRu-HESAC is confirmed by X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), and scanning transmission electron microscopy (STEM). Experimental results show that the HESAC has overpotentials of 0.41 and 0.37 V in acidic and alkaline electrolytes, respectively, with Tafel slopes of 101 and 210 mV dec\(^{-1}\) at a current density of 1 mA cm\(^{-2}\). These values are comparable to those of Pt/C. The HESAC is also tested in a Zinc-air battery, achieving an open circuit potential of 1.39 V and a power density of 0.16 W cm\(^{-2}\). The study demonstrates a rational design strategy for HESACs that can replace high-cost Pt catalysts in ORR and beyond.