The preparation, characterization, and catalytic properties of Pd nanoparticles supported on mesoporous organic–inorganic hybrid materials are described for continuous-flow aerobic oxidation of alcohols using supercritical carbon dioxide (scCO 2) as a mobile phase. The nanoparticles were generated “bottom-up” from molecular precursors that were precoordinated to the support through suitable anchor units. The most active material allows high single-pass conversions in scCO 2 at temperatures as low as 60 °C. This high activity may be associated with the presence of small primary crystallites (approx. 2 nm) that conglomerate to ensembles about 25 nm in size, leading to a larger number of high-indexed planes in small volume units. These findings may provide useful guidelines for further catalyst design on the nanoscale for green oxidation methods.