Highly reactive dense Pt single-atoms stabilized on an oxide support can resolve a grand challenge in the economic use of Pt in catalysis. The maximized number density of reaction sites provided by dense Pt single-atoms guarantees the improved catalytic performance of Pt combined with high efficiency. By manipulating the chemical nature of multi-component interfaces, we synthesized CO-tolerant dense Pt single-atoms highly reactive for the CO oxidation reaction, which governs the key steps for chemical energy conversion and emission control. The addition of 1 wt% of Ce to TiO₂ support particles creates a CeO_x–TiO₂ interface that stabilizes Pt single-atoms by strong electronic interactions. Dense Pt single-atoms formed on CeO_x/TiO₂ oxides exhibit 15.1 times greater specific mass activity toward CO oxidation at 140 °C compared with a bare Pt/TiO₂ catalyst. We elaborate how the CeO_x–TiO₂ interfaces activate the interface-mediated Mars–van Krevelen mechanism of CO oxidation and protect Pt single-atoms from CO-poisoning. Through a comprehensive interpretation of the formation and activation of dense Pt single-atoms using operando X-ray absorption spectroscopy, density functional theory calculations, and experimental catalyst performance tests, we provide a key that enables the catalytic performance of noble metal single-atom catalysts to be optimized by atomic-scale tuning of the metal–support interface.