Abstract The urgent demand for designing highly efficient electrocatalysts for ethanol oxidation reaction (EOR) with elevated C1 selectivity, robust anti‐poisoning capability, and high mass activity presents a formidable challenge. Herein, a novel two‐dimentional (2D) high‐entropy PdRhFeCoMo metallene (PdRhFeCoMo HEM) electrocatalyst is successfully synthesized via a mild one‐step solvothermal method. The PdRhFeCoMo HEM, characterized by intentionally designed multi‐metallic ensembles and ultra‐thin graphene‐like structures, delivers an impressive mass activity of 7.47 A mg Pd+Rh −1 and specific activity of 25.5 mA cm −2 . Furthermore, it can retain a mass activity of 0.56 A mg Pd+Rh −1 after undergoing 20000 s of continuous testing, demonstrating outstanding resistance to poisoning. More significantly, the PdRhFeCoMo HEM demonstrates an elevated capacity for C─C bond cleavage with a superior C1 selectivity of up to 84.12%. In situ spectroscopy analysis, combined with theoretical calculations, reveals that the deliberate design of components and structures effectively regulate the electronic properties of the Pd site, thereby enhancing the adsorption of reactant and reducing the reaction barrier of the C1 pathway. Finally, a flexible solid‐state ethanol fuel cell assembled by PdRhFeCoMo HEM presents a maximum power density of 20.1 mW cm −2 and can operate continuously by repeatedly adding ethanol fuel.