Amidst rising water demands, which have historically been met by expanding surface water reservoir storage, society’s reliance on groundwater usage has increased by 50% globally over the last 50 years. Here, we seek to understand how groundwater (and surface water) supply might evolve into the future globally under an array of uncertain human and Earth system forces, such as socioeconomic and technological change and climate impacts on water availability. To do this, we use the Global Change Analysis Model (GCAM) – an integrated model of the human-Earth system that represents the dynamic interactions between socioeconomic, energy, land, water, and climate systems at global scale within an internally consistent economic modeling framework. Using a large ensemble of 900 GCAM simulations that spans a diversity of uncertain human and Earth system dimensions of global change, we use scenario discovery techniques to identify scenarios that lead to challenging outcomes with regard to the magnitude and timing of peak nonrenewable groundwater extraction and its consequences (e.g., for water scarcity and prices, food prices, and land use). We find that at global scale, the magnitude of peak groundwater extraction is driven by supply-side uncertainties such as the cost and availability of surface water reservoir storage and the degree to which groundwater usage is constrained (e.g., on the basis of socio-environmental concerns). Conversely, the timing of peak groundwater extraction is driven by demand-side uncertainties such as the Shared Socioeconomic Pathways (SSPs) and Representative Concentration Pathways (RCPs). Regionally (i.e., across 235 global river basins), the composition of challenging scenarios differs substantially, including some in which uncertainty around historical groundwater depletion rates are critical (Indus basin), and some in which climate change impacts on surface water are critical (Missouri basin). Groundwater challenges in the western United States, Mexico India, China, Pakistan, and the Middle East, such as exhaustion of economically accessible groundwater and rapidly approaching peaks in groundwater withdrawals, could have strong implications for the future of surface water storage and use on other continents.