Here, we report facile fabrication of two-dimensional (2D) Pd nanosheet (NS)-supported zero-dimensional (0D) Au nanoparticles via galvanic replacement. In the synthesis, the surface-clean Pd NSs premade not only acted as a sacrifice template for replacing Pd atoms by Au3+ ions, but served as a support substrate to support Au nanoparticles. The morphology, structure, and composition of products relied on the Au/Pd feed atomic ratio. Interestingly, the as-obtained 0D/2D AuxPd100–x (x = 4.5, 9.8, and 21) nanocomposites showed remarkably enhanced peroxidase-mimic catalysis in the model oxidation reaction, which followed the typical Michaelis–Menten theory. Compared to Pd NSs, the enhanced catalysis of AuxPd100–x was closely related to both the increased specific surface area and the modified electronic structure of Pd NSs, which resulted in a change in the catalytic pathway, that is, from hydroxyl radical generation to rapid electron transfer. The work provides a simple yet efficient avenue to build highly efficient heterogeneous catalysts based on metallic NSs, as exemplified by the superior nanozyme activity of 0D/2D bimetallic nanostructures for glucose detection.