Developing platinum-based electrocatalysts with high CO tolerance for methanol oxidation reaction (MOR) is crucial for the practical application of direct methanol fuel cells (DMFCs). Herein, we employed a straightforward one-step method to synthesize PtxCuy network nanowires (NWNs), which exhibit the advantages of structural stability and bimetallic ensembles. The synergistic effect of compressive strain and the ligand effect, induced by Cu incorporation, can effectively lower the d-band center of Pt, thereby weakening the adsorption strength of CO on the catalyst surface. The optimized Pt42Cu58 NWNs deliver a peak mass activity of 1.33 A mgPt-1 and a specific activity of 4.43 mA cm-2 for MOR, which are 3.03 and 4.03 times higher than those of commercial Pt/C, respectively. The CO stripping and in-situ Fourier transform infrared spectroscopy results indicate its high anti-CO poisoning ability and methanol activation capacity. Moreover, the Pt42Cu58 NWNs also exhibit an excellent stability with high current densities observed after 3600 s operation due to the enhanced CO tolerance and the stable three-dimensional (3D) network structure. This work provides a feasible strategy to suppress CO poisoning during MOR and obtain highly efficient anode catalysts with enhanced durability in the DMFC fields.