This study reports the synthesis and characterization of single-atom Mo-tailored PdPtNiCuZn high-entropy-alloy (HEA) ultrathin nanosheets (NSs) with intrinsic tensile strain, which exhibit enhanced electrocatalytic activity for methanol oxidation reaction (MOR). The as-synthesized Mo1-PdPtNiCuZn SAHEA NSs show an extraordinary mass activity of 24.55 A mgPt−1 and 11.62 A mgPt+Pt−1, significantly higher than commercial Pt/C catalysts. The presence of isolated Mo single atoms as promoters modifies the electronic structure of isolated Pt sites, suppressing CO adsorption and promoting the formate pathway. The intrinsic tensile strain optimizes the adsorption behavior of intermediates, further enhancing the catalytic performance. The combination of Mo single atoms and tensile strain creates a favorable electronic microenvironment, switching the MOR to a CO-free dominated pathway and improving the reaction kinetics and thermodynamics. The study demonstrates a novel strategy for designing atomically precise catalytic sites by tailoring single-atom Mo in HEA NSs, offering a promising approach for developing CO-tolerant electrocatalysts.This study reports the synthesis and characterization of single-atom Mo-tailored PdPtNiCuZn high-entropy-alloy (HEA) ultrathin nanosheets (NSs) with intrinsic tensile strain, which exhibit enhanced electrocatalytic activity for methanol oxidation reaction (MOR). The as-synthesized Mo1-PdPtNiCuZn SAHEA NSs show an extraordinary mass activity of 24.55 A mgPt−1 and 11.62 A mgPt+Pt−1, significantly higher than commercial Pt/C catalysts. The presence of isolated Mo single atoms as promoters modifies the electronic structure of isolated Pt sites, suppressing CO adsorption and promoting the formate pathway. The intrinsic tensile strain optimizes the adsorption behavior of intermediates, further enhancing the catalytic performance. The combination of Mo single atoms and tensile strain creates a favorable electronic microenvironment, switching the MOR to a CO-free dominated pathway and improving the reaction kinetics and thermodynamics. The study demonstrates a novel strategy for designing atomically precise catalytic sites by tailoring single-atom Mo in HEA NSs, offering a promising approach for developing CO-tolerant electrocatalysts.