High‐resolution regional‐scale hydrologic models were used to quantify the response of late 21st century runoff from the Gulf of Alaska (GOA) watershed to changes in regional climate and glacier extent. NCEP Climate Forecast System Reanalysis data were combined with five Coupled Model Intercomparison Project Phase 5 general circulation models (GCMs) for two representative concentration pathway (RCP) scenarios (4.5 and 8.5) to develop meteorological forcing for the period 2070–2099. A hypsographic model was used to estimate future glacier extent given assumed equilibrium line altitude (ELA) increases of 200 and 400 m. GCM predictions show an increase in annual precipitation of 12% for RCP 4.5 and 21% for RCP 8.5, and an increase in annual temperature of 2.5°C for RCP 4.5 and 4.3°C for RCP 8.5, averaged across the GOA. Scenarios with perturbed climate and glaciers predict annual GOA‐wide runoff to increase by 9% for RCP4.5/ELA200 case and 14% for the RCP8.5/ELA400 case. The glacier runoff decreased by 14% for RCP4.5/ELA200 and by 34% for the RCP8.5/ELA400 case. Intermodel variability in annual runoff was found to be approximately twice the variability in precipitation input. Additionally, there are significant changes in runoff partitioning and increases in snowpack runoff are dominated by increases in rain‐on‐snow events. We present results aggregated across the entire GOA and also for individual watersheds to illustrate the range in hydrologic regime changes and explore the sensitivities of these results by independently perturbing only climate forcings and only glacier cover.