<p>The methanol oxidation reaction is the bottleneck for direct methanol fuel cells. Unfortunately, the state-of-the-art Pt-based catalysts suffer heavily from the CO poisoning problem. Isolating Pt atoms in a material can avoid CO poisoning. However, single-atom Pt catalysts alone are inert towards methanol oxidation reaction. Here, we report high-entropy alloyed single-atom Pt catalysts, in which single-atom Pt sites are alloyed with non-noble elements in a high-entropy structure. This catalyst not only possesses active Pt sites but also inherits the ability of single-atom Pt to resist CO poisoning. Consequently, the catalyst shows a notable mass activity of 35.3 A mg⁻¹ at only 2.3 at% Pt and maintains high activity even after operation for 180,000 s. Both experimental and theoretical results reveal that the high-entropy structure induces a synergistic effect, wherein the elements coordinated around single-atom Pt sites effectively remove adsorbed CO from Pt. This mechanism facilitates the key reaction steps of methanol oxidation reaction and avoids CO poisoning. This work presents a high-entropy alloyed single-atom strategy to realize efficient and durable methanol oxidation reaction catalysis with low costs.</p>