Streamflows have increased notably across the U.S. Midwest over the past century, fueling a debate on the relative influences of changes in precipitation and land cover on the flow distribution. Here, we propose a simple modeling framework to evaluate the main drivers of streamflow rates. Streamflow records from 290 long-term USGS stream gauges were modeled using five predictors: precipitation, antecedent wetness, temperature, agriculture, and population density. We evaluated which predictor combinations performed best for every site, season and streamflow quantile. The goodness-of-fit of our models is generally high and varies by season (higher in the spring and summer than in the fall and winter), by streamflow quantile (best for high flows in the spring and winter, best for low flows in the fall, and good for all flow quantiles in summer), and by region (better in the southeastern Midwest than in the northwestern Midwest). In terms of predictors, we find that precipitation variability is key for modeling high flows, while antecedent wetness is a crucial secondary driver for low and median flows. Temperature improves model fits considerably in areas and seasons with notable snowmelt or evapotranspiration. Finally, in agricultural and urban basins, harvested acreage and population density are important predictors of changing streamflow, and their influence varies seasonally. Thus, any projected changes in these drivers are likely to have notable effects on future streamflow distributions, with potential implications for basin water management, agriculture, and flood risk management.