Flow regulation and irrigation alter local freshwater conditions, but their global effects are highly uncertain. We investigated these global effects from 1901 to 2008, using hydroclimatic observations in 100 large hydrological basins. Globally, we find consistent and dominant effects of increasing relative evapotranspiration from both activities, and decreasing temporal runoff variability from flow regulation. The evapotranspiration effect increases the long-term average human consumption of fresh water by 3563 ± 979 km³/year from 1901–1954 to 1955–2008. This increase raises a recent estimate of the current global water footprint of humanity by around 18%, to 10,688 ± 979 km³/year. The results highlight the global impact of local water-use activities and call for their relevant account in Earth system modeling.