Water is essential for the world’s food supply, for energy production, including bioenergy and hydroelectric power, and for power system cooling. Water is already scarce in many regions of the world and could present a critical constraint as society attempts simultaneously to mitigate climate forcing and adapt to climate change, and to provide for a larger and more prosperous human population. Numerous studies have pointed to growing pressures on the world’s scarce fresh water resources from population and economic growth, and climate change. This study goes further. We use the Global Change Assessment Model to analyze interactions between population, economic growth, energy, land, and water resources simultaneously in a dynamically evolving system where competing claims on water resources from all claimants—energy, land, and economy—are reconciled with water resource availability—from renewable water, non-renewable groundwater and desalinated water sources —across 14 geopolitical regions, 151 agriculture-ecological zones, and 235 major river basins. We find that previous estimates of global water withdrawal projections are overestimated. Model simulations show that it is more economical in some basins to alter agricultural and energy activities rather than utilize non-renewable groundwater or desalinated water. This study highlights the importance of accounting for water as a binding factor in agriculture, energy and land use decisions in integrated assessment models and implications for global responses to water scarcity, particularly in the trade of agricultural commodities and land-use decisions.