Porous multimetallic alloyed nanostructures possess unique physical and chemical properties to generate promising potential in fuel cells. However, the controllable synthesis of this kind of materials still remains challenging. Herein, we report a facile method for the one-pot, high-yield synthesis of trimetallic PtPdRh mesoporous nanospheres (PtPdRh MNs) under mild conditions. The resultant PtPdRh MNs possess the features of uniform shape, a narrow size distribution, plenty of well-defined mesopores, highly open structure, and multicomponent effects, which impart advantages such as large surface area, favorable mass diffusion, high utilization of electrocatalysts, and synergy among the various metal components. Benefitting from the synergetic effects originating from the multimetallic composition and unique mesoporous structure, the as-prepared PtPdRh MNs exhibit remarkably enhanced electrocatalytic performance for methanol oxidation reaction relative to bimetallic PtPd MNs and commercial Pt/C catalyst.