An unprecedented substrate-selective catalytic enhancement effect of an alkanethiol-self-assembled monolayer (SAM) on Au nanoparticles (AuNPs) is reported. In the supported 2D-array of AuNPs, the alkanethiol-SAM acts as a protein-like soft reaction space in which the substrate molecules are encapsulated through non-covalent intermolecular hydrophobic interactions, and thus catalytic reactions are accelerated at AuNP surfaces.