Pt-based catalysts for methanol fuel electrooxidation typically suffer from CO intermediate poisoning. Herein, we incorporated secondary Ni element into PtPd hollow nanocrystals (HNCs) to fabricate a trimetallic NiPtPd-HNCs catalyst with superior CO tolerance and high activity for methanol electro-oxidation. The as-prepared trimetallic NiPtPd-HNCs exhibit promising specific and mass activity of 10.68 mA•cm −2 and 3.95 A•mg Pd+Pt −1, respectively, which is 4.2and 4.5-fold higher than that of commercial Pt/C. Notably, CO-stripping tests and 3000 s chronoamperometry experiments in a rigorous CO-saturated medium show that trimetallic NiPtPd-HNCs possess higher CO tolerance compared with that of the bimetallic counterparts. Ultimately, we ascribed to the enhanced activity and CO tolerance of trimetallic NiPtPd-HNCs to (i) the preponderance of hollow interior and dendritic morphology, (ii) the considerably improved binding energy of OH ads on NiPtPd surface which is beneficial to the removal of the partial oxidation intermediates during the methanol electrooxidation, and (iii) the modification of the electronic structure of Pt and Pd caused by Ni heteroatoms exposure to surface. The employment of Ni may be extended to the rational development of other Pt-based multimetallic nanocrystals with high CO tolerance and promising activity in the small molecules fuel electro-oxidation.