The U.S. Geological Survey, in cooperation with the Lewis and Clark, Lower Elkhorn, Lower Loup, Lower Platte North, Lower Niobrara, Middle Niobrara, Upper Elkhorn, and the Upper Loup Natural Resources Districts, designed a study to refine the spatial and temporal discretization of a previously modeled area. This updated study focused on a 30,000-square-mile area of the High Plains aquifer and constructed regional groundwater-flow models to evaluate the effects of groundwater withdrawal on stream base flow in the Elkhorn and Loup River Basins, Nebraska. The model was calibrated to match groundwater-level and base-flow data from the stream-aquifer system from pre-1940 through 2010 (including predevelopment [pre-1895], early development [1895-1940], and historical development [1940 through 2010] conditions) using an automated parameter-estimation method. The calibrated model then was used to simulate hypothetical development conditions (2011 through 2060). Predicted changes to stream base flow based on simulated changes to groundwater withdrawal will aid in developing strategies for management of hydrologically connected water supplies. Additional wells were simulated throughout the model domain and pumped for 50 years to assess the effect of wells on aquifer depletions, including stream base flow. The percentage of withdrawal for each well after 50 years, which was compensated by aquifer reductions to stream base flow, storage, or evapotranspiration, was computed and mapped. These depletions are influenced by aquifer properties, time, and distance from the well. Stream base-flow depletion results showed that the closer the added well was to a stream, the greatest the effect on the stream base flow. Areas of stream base-flow depletion percentages greater than 80 percent were generally within 1 mile (mi) from the stream. The distance increased to 6 mi near the confluence of the Dismal and Middle Loup Rivers, and the North Loup and Calamus Rivers. The percentage of stream base-flow depletion decreased as the distance from the stream increased. Areas more than 10 mi from the stream generally had a stream base-flow depletion of 10 percent or less. Evapotranspiration depletion was largest in areas closest to streams, specifically in the Elkhorn River watershed. It was also larger in areas of interdunal wetlands within the Sand Hills. Evapotranspiration depletion was negligible in areas greater than 5 mi from a stream, with the exception of interdunal areas in Cherry, Grant, and Arthur Counties. The storage depletion percentage increased as the distance from a stream increased. Storage depletion was largest in areas between streams. Areas experiencing the smallest amount of storage depletion were adjacent to streams. Calibrated model outputs and streamflow depletion analysis are publicly available online. Accuracy of the simulations is affected by input data limitations, system simplifications, assumptions, and resources available at the time of the simulation construction and calibration. Most of the important limitations relate either to data used as simulation inputs or to data used to estimate simulation inputs. Development of the regional simulations focused on generalized hydrogeologic characteristics within the study area and did not attempt to describe variations important to local-scale conditions. These simulations are most appropriate for analyzing groundwater-management scenarios for large areas and during long periods and are not suitable for analysis of small areas or short periods.