AbstractSingle cluster catalysts (SCCs) consisting of atomically precise metal nanoclusters dispersed on supports represent a new frontier of heterogeneous catalysis. However, the ability to synthesize SCCs with high loading and to precisely introduce non‐metal atoms to further tune their catalytic activity and reaction scope of SCCs have been longstanding challenges. Here, a new interface confinement strategy is developed for the synthesis of a high density of atomically precise Ru oxide nanoclusters (Ru₃O₂) on reduced graphene oxide (rGO), attributed to the suppression of diffusion‐induced metal cluster aggregation. Ru₃O₂/rGO exhibits a significantly enhanced activity for oxidative dehydrogenation of 1,2,3,4‐tetrahydroquinoline (THQ) to quinoline with a high yield (≈86%) and selectivity (≈99%), superior to Ru and RuO₂ nanoparticles, and homogeneous single/multiple‐site Ru catalysts. In addition, Ru₃O₂/rGO is also capable of efficiently catalyzing more complex oxidative reactions involving three reactants. The theoretical calculations reveal that the presence of two oxygen atoms in the Ru₃O₂ motif not only leads to a weak hydrogen bonding interaction between the THQ reactant and the active site, but also dramatically depletes the density of states near the Fermi level, which is attributed to the increased positive valence state of Ru and the enhanced oxidative activity of the Ru₃O₂ cluster for hydrogen abstraction.