We develop a data-driven approach to robustly assess freshwater changes due to climate change and/or human irrigation developments by use of the overarching constraints of catchment water balance. This is applied to and tested in the high-uncertainty case of Greece for five nested catchments of different scales across the country and for freshwater changes from an early period (1930–1949) with small human influences on climate and irrigation to a recent period (1990–2009) with expected greater such influences. The results show more or less equal contributions from climatic decrease in precipitation and from human irrigation development to a considerable total decrease in runoff (R) over Greece. This is on average −75 ± 10 mm/year and is greatest for the Ionian catchment in the west (−119 ± 18 mm/year) and the Peloponnese catchment in the south (−91 ± 16 mm/year). For evapotranspiration (ET), a climate-driven decrease component and an irrigation-driven increase component have led to a net total increase of ET over Greece. This is on average 26 ± 7 mm/year and is greatest for the Mainland catchment (29 ± 7 mm/year) and the Aegean catchment in the east (28 ± 6 mm/year). Overall, the resulting uncertainties in the water-balance constrained estimates of R and ET changes are smaller than the input data uncertainties.