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Complete transformations of land cover from prairie, wetlands, and hardwood forests to row crop agriculture and urban centers are thought to have caused profound changes in hydrology in the Upper Midwestern US since the 1800s. In this study, we investigate four large (23 000–69 000 km²) Midwest river basins that span climate and land use gradients to understand how climate and agricultural drainage have influenced basin hydrology over the last 79 years. We use daily, monthly, and annual flow metrics to document streamflow changes and discuss those changes in the context of precipitation and land use changes. Since 1935, flow, precipitation, artificial drainage extent, and corn and soybean acreage have increased across the region. In extensively drained basins, we observe 2 to 4 fold increases in low flows and 1.5 to 3 fold increases in high and extreme flows. Using a water budget, we determined that the storage term has decreased in intensively drained and cultivated basins by 30–200 % since 1975, but increased by roughly 30 % in the less agricultural basin. Storage has generally decreased during spring and summer months and increased during fall and winter months in all watersheds. Thus, the loss of storage and enhanced hydrologic connectivity and efficiency imparted by artificial agricultural drainage appear to have amplified the streamflow response to precipitation increases in the Midwest. Future increases in precipitation are likely to further intensify drainage practices and increase streamflows. Increased streamflow has implications for flood risk, channel adjustment, and sediment and nutrient transport and presents unique challenges for agriculture and water resource management in the Midwest. Better documentation of existing and future drain tile and ditch installation is needed to further understand the role of climate versus drainage across multiple spatial and temporal scales.