This study presents a novel class of single-atom Mo-tailored high-entropy-alloy (HEA) ultrathin nanosheets with intrinsic tensile strain, which significantly enhances the electrocatalytic performance for the methanol oxidation reaction (MOR). The Mo₁-PdPtNiCuZn HEA nanosheets exhibit exceptional mass activity of 24.55 A mg⁻¹ Pt and 11.62 A mg⁻¹ Pd+Pt, along with remarkable long-term durability. The oxophilic Mo single atoms act as promoters, modifying the electronic structure of isolated Pt sites in the HEA host, suppressing CO adsorbates and steering the reaction towards the formate pathway. The intrinsic tensile strain synergistically optimizes the adsorption behavior of intermediates, achieving a more energetically favorable pathway and minimizing the MOR reaction barrier. This work advances the design of atomically precise catalytic sites by creating a new paradigm of single atom-tailored high-entropy alloys, opening an encouraging pathway to the design of CO-tolerant electrocatalysts. The study also demonstrates the synthesis of various SAHEA nanosheets, including senary and septenary compositions, with high structural and compositional stability. The Mo₁-PdPtNiCuZn SAHEA nanosheets show superior electrocatalytic performance compared to commercial Pt/C catalysts, with a mass activity 18.13 and 8.58 times higher, respectively. The MOR performance is further confirmed by in-situ FTIR spectroscopy, which reveals the formation of formate intermediates and the absence of CO adsorbates, indicating the successful switch to a CO-free pathway. Density functional theory (DFT) calculations support the enhanced MOR performance by showing the optimized electronic structure and the up-shifted d-band center of the Mo₁-PdPtNiCuZn nanosheets, which facilitate the adsorption of intermediates and enhance the reaction kinetics. The study highlights the importance of combining single-atom modification with intrinsic tensile strain in HEA nanosheets to achieve high-performance electrocatalysts for MOR. The results demonstrate that the Mo₁-PdPtNiCuZn SAHEA nanosheets not only exhibit high activity and stability but also show excellent CO tolerance, making them promising candidates for application in direct methanol fuel cells and other energy conversion devices. The findings provide a new strategy for the design of high-performance electrocatalysts with enhanced catalytic performance for a wide range of applications.This study presents a novel class of single-atom Mo-tailored high-entropy-alloy (HEA) ultrathin nanosheets with intrinsic tensile strain, which significantly enhances the electrocatalytic performance for the methanol oxidation reaction (MOR). The Mo₁-PdPtNiCuZn HEA nanosheets exhibit exceptional mass activity of 24.55 A mg⁻¹ Pt and 11.62 A mg⁻¹ Pd+Pt, along with remarkable long-term durability. The oxophilic Mo single atoms act as promoters, modifying the electronic structure of isolated Pt sites in the HEA host, suppressing CO adsorbates and steering the reaction towards the formate pathway. The intrinsic tensile strain synergistically optimizes the adsorption behavior of intermediates, achieving a more energetically favorable pathway and minimizing the MOR reaction barrier. This work advances the design of atomically precise catalytic sites by creating a new paradigm of single atom-tailored high-entropy alloys, opening an encouraging pathway to the design of CO-tolerant electrocatalysts. The study also demonstrates the synthesis of various SAHEA nanosheets, including senary and septenary compositions, with high structural and compositional stability. The Mo₁-PdPtNiCuZn SAHEA nanosheets show superior electrocatalytic performance compared to commercial Pt/C catalysts, with a mass activity 18.13 and 8.58 times higher, respectively. The MOR performance is further confirmed by in-situ FTIR spectroscopy, which reveals the formation of formate intermediates and the absence of CO adsorbates, indicating the successful switch to a CO-free pathway. Density functional theory (DFT) calculations support the enhanced MOR performance by showing the optimized electronic structure and the up-shifted d-band center of the Mo₁-PdPtNiCuZn nanosheets, which facilitate the adsorption of intermediates and enhance the reaction kinetics. The study highlights the importance of combining single-atom modification with intrinsic tensile strain in HEA nanosheets to achieve high-performance electrocatalysts for MOR. The results demonstrate that the Mo₁-PdPtNiCuZn SAHEA nanosheets not only exhibit high activity and stability but also show excellent CO tolerance, making them promising candidates for application in direct methanol fuel cells and other energy conversion devices. The findings provide a new strategy for the design of high-performance electrocatalysts with enhanced catalytic performance for a wide range of applications.