A key challenge for direct methanol fuel cells is the sluggish reaction kinetics, poor anti-CO poisoning ability, and insufficient Pt utilization of platinum-based catalysts during methanol oxidation reaction (MOR). Herein, we report a facile approach for PtCuNi electrocatalysts with adjustable inner and surface configurations. By judiciously controlling the nucleation/growth kinetics, PtCuNi core-shell alloy nanoparticles (PtCuNi-CS NPs) fortified with a Cu-rich core and a Pt-rich shell are obtained. Especially, PtCuNi-CS NPs show the highest mass activity and specific activity toward MOR, 5.7 and 5.1 times higher than those of commercial Pt/C. Density functional theory calculations reveal that the PtCuNi-CS NPs with a suitable d-band center possess excellent electro-oxidation activity. Additionally, the doping of Cu and Ni atoms endows the PtCuNi-CS NPs with enhanced OH* adsorption. This work provides an effective design strategy to develop Pt-based trimetallic electrocatalysts as efficient anode materials for fuel cell applications.