Over the past few decades, peroxidase mimics made of platinum-group metal nanoparticles (PGM NPs) have been actively developed and applied to various biosensing platforms. Nevertheless, there is a lack of a comprehensive study that compares the peroxidase-like activities of PGM NPs and their performance in biosensing. Here, we report a systematic study of PGM NPs as peroxidase mimics, including Pd, Pt, Rh, and Ir NPs. NPs of these elements were uniformly synthesized and their nanoscale features were probed to ensure a consistent size, shape, and chemical ligand on the surface. Our measurements indicate that the Ir NP is the most active one with a catalytic constant as high as 6.27 × 105 s–1, followed by Pt, Rh, and Pd NPs. The binding affinities of NPs to peroxidase substrates during catalysis were also quantitively analyzed and compared. Using enzyme-linked immunosorbent assay as a model biosensing platform, the performance of PGM NPs in detecting carcinoembryonic antigen (a cancer biomarker) was evaluated. The results showed that the detection sensitivity was correlated to the catalytic activity of PGM NPs, where Ir NPs achieved the highest sensitivity with a limit of detection at the level of low picogram per milliliter.