The Great Lakes basin hosts the world's most abundant surface fresh water reserve. Historically an industrial and natural resource powerhouse, the region has suffered economic stagnation in recent decades. Meanwhile, growing water resource scarcity around the world is creating pressure on water‐intensive human activities. This situation creates the potential for the Great Lakes region to sustainably utilize its relative water wealth for economic benefit. We combine economic production and trade datasets with water consumption data and models of surface water depletion in the region. We find that, on average, the current economy does not create significant impacts on surface waters, but there is some risk that unregulated large water uses can create environmental flow impacts if they are developed in the wrong locations. Water uses drawing on deep groundwater or the Great Lakes themselves are unlikely to create a significant depletion, and discharge of groundwater withdrawals to surface waters offsets most surface water depletion. This relative abundance of surface water means that science‐based management of large water uses to avoid accidentally creating “hotspots” is likely to be successful in avoiding future impacts, even if water use is significantly increased. Commercial water uses are the most productive, with thermoelectric, mining, and agricultural water uses in the lowest tier of water productivity. Surprisingly for such a water‐abundant economy, the region is a net importer of water‐derived goods and services. This, combined with the abundance of surface water, suggests that the region's water‐based economy has room to grow in the 21st century.