N2O exhibits unique reactivity in oxidation catalysis, but the high manufacturing costs limit its prospective uses. Direct oxidation of NH3 to N2O can ameliorate this issue but its implementation is thwarted by suboptimal catalyst selectivity and stability, and the lack of established structure-performance relationships. Systematic and controlled material nanostructuring offers an innovative approach for advancement in catalyst design. Herein we discover low-valent manganese atoms stabilized on ceria, CeO2, as the first stable catalyst for NH3 oxidation to N2O, exhibiting two-fold higher productivity than the state-of-the-art. Detailed mechanistic, computational and kinetic studies reveal CeO2 as the mediator of oxygen supply, while undercoordinated manganese species activate O2 and facilitate N2O evolution via N-N bond formation between nitroxyl, HNO, intermediates. Synthesis via simple impregnation of a small metal quantity (1 wt.%) predominantly generates isolated manganese sites, while full atomic dispersion is achieved upon redispersion of sporadic oxide nanoparticles during reaction, as confirmed by advanced microscopic analysis and electron paramagnetic resonance spectroscopy. Subsequently, manganese speciation is maintained, and no deactivation is observed over 70 h on stream. CeO2-supported isolated transition metals emerge as a novel class of materials for N2O production, encouraging future studies to evaluate their potential in selective catalytic oxidations at large.