Both climate change and human activities are known to have induced changes to hydrology. Consequently, quantifying the net impact of human contribution to the streamflow change is a challenge. In this paper, a decomposition method based on the Budyko hypothesis is used to quantify the climate (i.e., precipitation and potential evaporation change) and direct human impact on mean annual streamflow (MAS) for 413 watersheds in the contiguous United States. The data for annual precipitation, runoff, and potential evaporation are obtained from the international Model Parameter Estimation Experiment (MOPEX), which is often assumed to only include gauges unaffected by human interferences. The data are split into two periods (1948–1970 and 1971–2003) to quantify the change over time. Although climate is found to affect MAS more than direct human impact, the results show that assuming the MOPEX data set to be unaffected by human activities is far from realistic. Climate change causes increasing MAS in most watersheds, while the direct human-induced change is spatially heterogeneous in the contiguous United States, with strong regional patterns, e.g., human activities causing increased MAS in the Midwest and significantly decreased MAS in the High Plains. The climate- and human-induced changes are found to be more severe in arid regions, where water is limited. Comparing the results to a collection of independent data sets indicates that the estimated direct human impacts on MAS in this largely nonurban set of watersheds might be attributed to several human activities, such as cropland expansion, irrigation, and the construction of reservoirs.