Noble metal nanomaterials have been widely demonstrated to possess intrinsic enzyme-like properties and have been increasingly applied in the fields of analysis and biomedicine. However, current exploration of high-activity noble metal nanozymes is still far from adequate. The construction of hollow structures and adjustment of their elemental composition are effective ways to improve the specific activity (SA) of nanozymes. In this study, trimetallic PtPdAu hollow nanorods (HNRs) were developed using a galvanic replacement reaction and Kirkendall effect. The catalytic experiment showed that the PtPdAu HNRs possessed outstanding peroxidase-like performance and their SA value was up to 563.71 U mg, which is remarkable among various previously reported nanozymes and higher than that of monometallic or bimetallic counterparts with similar structure and size prepared in this study. Electron paramagnetic resonance (EPR)measurements showed that the PtPdAu HNRs could contribute to the formation of hydroxyl radicals (˙OH) in catalyzing hydrogen peroxide. When using PtPdAu HNRs as a nanozyme in the colorimetric detection of HO and ascorbic acid (AA), the limits of detection were as low as 1.8 μM and 0.068 μM, respectively. This study demonstrates that PtPdAu HNRs are high-activity nanozymes and have the potential to be applied in the field of analysis.