This study evaluated hydroclimate projections and effects on runoff at National Wildlife Refuges in a semiarid region of the western United States (U.S. Fish and Wildlife Service Region 6) using mean air temperature (TAVE) and precipitation (PPT) inputs and runoff (RO) output from a national application of a Monthly Water Balance Model (MWBM). An ensemble of statistically downscaled global circulation models for two future emissions scenarios from Coupled Model Intercomparison Project 3 and 5 (CMIP3 and 5) were assessed at the refuges for the years 1950–2099. TAVE, PPT, and RO and departures from mean baseline conditions were analyzed from MWBM hydrologic response units within refuge boundaries. Seasonal results were evaluated across four periods: historical (1951–1969), baseline (1981–1999), 2050 (2041–2059), and 2080 (2071–2089). Projected TAVE increases for all refuges and time periods, whereas PPT and RO are much more variable across ecoregions. Using the high emission scenario, summer mean monthly TAVE increases range from 4.8°C to 5.5°C by 2080. Summer mean monthly PPT departures vary from −5.7 to 3.9 mm (up to 14% decrease), with decreases at 41% of refuges. Summer RO departures range from −16.7 to 0.2 mm (up to 60% decrease), with decreases at 71% of refuges. Under the same emission scenario, winter PPT and RO increase at most refuges by 2080. These variable departures will create substantial challenges for future conservation management in the region.