There is a growing consensus that energy, water, and land systems are interconnected and should be analyzed as such. New tools are required to represent the interactions between population, economic growth, energy, land, and water resources in a dynamically evolving system. Here we use the Global Change Assessment Model (GCAM) to investigate the relative contributions of climate and human systems on water scarcity regionally and globally under a wide range of scenarios. The model accounts for a variety of human activities, including changing demands for water for agriculture, power generation, industry, and public supply. We find that these activities exert a larger influence on water scarcity than climate in 93% of river basins globally. This work highlights the importance of accounting for human activities in hydrologic modeling applications and how they may change under different pathways of how land use and agricultural systems, energy systems, and economies may evolve in the future.