The reactant-induced dynamics of catalysts under harsh conditions have a profound impact on their reactivity and stability, and identification of the underlying principle and active sites is vital for the rational design of catalysts. Based on a comprehensive first-principles investigation, we reveal here a reactant-induced dynamic stabilization of the highly dispersed Pt complexes that formed on ceria surfaces and their decisive role in CO oxidation. Compared to those of Pt nanoparticles, reactant-stabilized single-nuclear Pt1(CO)m and/or multinuclear Pt8(CO)n complexes prevail under CO-rich conditions on the defective CeO2 (111), (110), and (100) surfaces considered. At lower temperatures, the Pt1(CO) complexes emerge as active sites for CO oxidation, whereas at higher temperatures, the active sites transit dynamically to the Pt8(CO)9 complexes. We found that oxygen defects not only stabilize the complexes but also promote activity via the facile Mars–van Krevelen mechanism. These insights reveal the great impact of the reactant-interference structure–activity relationship under operando conditions.