The Upper Mississippi River Basin (UMRB) has experienced a remarkable agricultural extensification since the mid-1800s. Hydroclimatological monitoring in the 20th century also reveals positive annual precipitation and runoff trends in the UMRB. While several studies have proposed land use/land cover (LULC) change as the primary cause of runoff increase, little is known about the dominant controls of hydrologic change in the UMRB. We used a macroscale hydrology model to assess the hydrologic implications of climate and LULC changes between 1918 and 2007. Modeling results, corroborated with hydroclimatologic data analysis, emphasized climate change as the dominant driver of runoff change in the UMRB. At local scales, modeled annual runoff decreased (increased) by up to 9% (5%) where grasslands (forests) were replaced by croplands. Artificial field drainage amplified annual runoff by as much as 13%. These findings are critical for water and nitrogen management in the UMRB under change.