Preparation of high-density and atomically-dispersed clusters is of great importance yet remains a formidable challenge, which precludes rational design of high-performance, ultrasmall heterogeneous catalysts for alleviating the energy and environmental crises. In this study, we demonstrated an appealing non-equilibrium growth model to give sub-2 nm CuO clusters not from the growth of nuclei but from the top-down growth of metastable bulk crystals. These CuO clusters have high density and intriguingly uniform orientation, and are atomically scattered on an inactive ultrathin AlOOH substrate, which has been driven by the lattice matching between the CuO clusters and the utlrathin AlOOH substrate. The catalytic activity of CuO clusters, with the hydrogenation of 4-nitrophenol as a model reaction, proved to be extremely efficient and showed a rate constant of 130.0 s⁻¹ g⁻¹, outperforming the commercial Pd/C catalysts and reported state-of-the-art noble-metal catalysts (1.89–117.2 s⁻¹ g⁻¹). These clusters have abundant interfacial oxygen vacancies (OVs) whose concentration can be regulated, and the OVs are found to be essential, according to density functional theory (DFT) calculations, in reducing the energy barrier of catalytic reduction and significantly boosting the catalytic reaction. These findings could add to the library of crystals downsized to the atomic level and demonstrate how engineering point defects on the sub-nanometer materials help design high-efficient catalysts.