This study investigates the influence of climate change on groundwater availability, and thereby, irrigation across political boundaries within the United States’ High Plains aquifer. A regression model is developed to predict changes in irrigation according to predicted changes in precipitation and temperature from a downscaled dataset of 32 general circulation models (GCMs). Precipitation recharge changes are calculated with precipitation-recharge curves developed for prognostic representations of precipitation across the Nebraska-Colorado-Kansas area and within the Republican River Basin focal landscape. Irrigation-recharge changes are scaled with changes in irrigation. The groundwater responses to climate forcings are then simulated under new pumping and recharge rates using a MODFLOW groundwater flow model. Results show that groundwater pumping and recharge both will increase and that the effects of groundwater pumping will overshadow those from natural fluctuations. Groundwater levels will decline more in areas with irrigation-driven decreasing trends in the baseline. The methodologies and predictions of this study can inform long-term water planning and the design of management strategies that help avoid and resolve water-related conflicts, enabling irrigation sustainability.