Abstract Climate change predicts more frequent drought spells along with an elevation in atmospheric CO2 concentration (e[CO2]). Although the responses of winter wheat (Triticum aestivum L.) plants to drought or a single generation exposure to e[CO2] have been well documented, the transgenerational effect of e[CO2] in combination of drought on stomatal behavior, plant water consumption and water use efficiency (WUE) have not been investigated. Seeds harvested from plants after two generations (2014–2015) continuously grown in ambient CO2 (a[CO2], 400 μmol L−1) and e[CO2] (800 μmol L−1) were sown in 4 L pots, and the plants were grown separately in greenhouse cells with either a[CO2] or e[CO2]. At stem elongation stage, in each of the cells half of the plants were subjected to progressive drought stress until all the plant available soil water was depleted, and the other half were well-watered and served as controls. The results showed that transgenerational exposure of the winter wheat plants to e[CO2] could attenuate the negative impact of drought stress on dry biomass (DM) and WUE. The modulations of multi-generational e[CO2] on leaf abscisic acid concentration, stomatal conductance, and leaf water status could have contributed to the enhanced DM and WUE. These findings provide new insights into the response of wheat plants to a future drier and CO2-enriched environment.