Floods are among humanity’s costliest natural disasters. Anthropogenic global change, including both climate change and land-use change, can alter hydrologic regimes, but global changes are overlain on natural climatic fluctuations and can have competing influences on streamflow, making it difficult to understand and prepare for hydrologic change. In the Missouri River basin, one of the largest river systems in the United States (U.S.), average streamflow increased by ~40% over the past century, with multiple years of extremely high streamflow occurring since 1990. We investigated the causes of increased Missouri River streamflow, finding that it was mostly driven by “natural” climate variability and by land-use change (replacement of deep-rooted forests and shrublands by shallow-rooted croplands and grasslands), whereas anthropogenic climate trends would have caused drying, all else being equal. This implies that when the current multi-decade wet period ends, the Missouri basin could return to a drier mean state made worse by human-caused warming.