Significance Devising sustainable climate change mitigation policies with attention to potential synergies and constraints within the climate–energy–water nexus is the subject of ongoing integrated modeling efforts. This study employs a regional integrated assessment model and a regional Earth system model at high spatial and temporal resolutions in the Unites States to compare the implications of two of the representative concentration pathways under consistent socioeconomics. The results clearly show, for the first time to our knowledge, that climate change mitigation policies, if not designed with careful attention to water resources, could increase the magnitude, spatial coverage, and frequency of water deficits. The results challenge the general perception that mitigation that aims at reducing warming also would alleviate water deficits in the future.