Exploring high-efficiency, robust and cost-efficient anode catalysts for direct methanol fuel cells (DMFCs) is extremely urgent and challenging. Here we report a rational design of hierarchically structured platinum–nickel@platinum–tin core@shell nanowires (H-PtNi@PtSn NWs) for efficient methanol oxidation reaction (MOR) and membrane electrode assembly (MEA) catalysis in DMFCs. In particular, the H-PtNi@PtSn NWs demonstrate exceptional mass and specific activities of 3.35 A mg_Pt⁻¹ and 3.42 mA cm⁻² for the MOR, along with high stability with limited 18.5% mass activity decay after nine consecutive chronoamperometry cycles for 18 000 s. More importantly, they can realize a MEA power density of 65.1 mW cm⁻² in a single DMFC, better than those of commercial Pt/C and many other reported Pt-based catalysts, revealing promising device application potential. The integration of advantageous hierarchical configuration and the unique core@shell structure effectively avoids the inherent issues of traditional PtNi nanostructures such as limited active sites and poor CO-tolerance. The in situ Fourier transform infrared spectroscopy and CO-stripping measurements collectively reveal that the H-PtNi@PtSn NWs can weaken the chemisorption of the adsorbed CO intermediate and promote its oxidation removal, simultaneously encouraging the “CO free” pathway, thereby boosting the MOR performance and achieving efficient MEA catalysis for DMFCs.