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The Gulf Coast watersheds in the United States contain some of the highest levels of biodiversity of all freshwater systems in North America. Developing environmental management policies to protect and preserve these ecosystems makes the study of the impacts of projected climate change on the future hydrologic cycle crucial. We used the Soil and Water Assessment Tool (SWAT) to estimate the potential hydrologic changes for the mid-21st century (2050s) and the late 21st century (2080s) in the Mobile River, Apalachicola River, and Suwannee River watersheds in the Gulf Coast region of the United States. These estimates are based on downscaled future climate projections from 20 global circulation models (GCMs) under two representative concentration pathways (RCPs 4.5 and 8.5). SWAT models were calibrated and validated using the multi-algorithm, genetically adaptive multi-objective (AMALGAM) technique in a high-performance computing (HPC) cluster. For the Gulf Coast watersheds, the climate is projected to be warmer and wetter. Projected changes in climatic variables are likely to bring large changes in both annual and seasonal hydrologic processes within these watersheds. We found substantial decreases in mean annual streamflow under RCP8.5 during the 2080s, with up to a 13.0% decrease projected for the Suwannee River watershed compared to the present day. Summer streamflow is projected to be substantially lower during the 2080s, with up to a 25.1% decrease projected for the Suwannee River watershed, during a time of high demand of water resources for agricultural, industrial, and ecosystem services. These hydrologic projections are expected to help in making better-informed decisions for future water resources and ecosystem management in the Gulf Coast region.