By using first-principles thermodynamics calculations, we investigate the structural evolution of active sites on Cu/ZnO surfaces from reactive environment to ultrahigh vacuum conditions. Under O-rich conditions, the formation of active oxygen vacancies on various ZnO surfaces is unfavorable. However, addition of Cu dopants can significantly improve the reducibility of the ZnO nonpolar and polar surfaces, to an extent that ZnO(0 0 0 1)–O polar surface can be fully reduced. The formed oxygen vacancies in turn enhance the charging of Cu active sites on the highly dispersed metallic monolayers containing Cu and Zn. This is believed to be a factor contributing to the synergetic effects of Cu/ZnO catalysts. Irreversible reconstruction of the active metallic monolayers would take place upon removal from the reactive environment and exposure to ultrahigh vacuum condition, resulting in less active Cu overlayers. Therefore, experiments performed directly under UHV conditions may underestimate the activity of the actual catalysts under reactive environment.