We present a regional framework for an integrated and spatiotemporally distributed assessment of human-induced trends in the hydrology and the associated ecological health of a semi-arid basin where both human activities (i.e. agriculture) and natural ecosystems are highly groundwater dependent. To achieve this, we analysed the recent trends (from year 2000 to 2010) in precipitation, evapotranspiration (actual and potential) and vegetation greenness (i.e. NDVI) using a combination of satellite and ground-based observations. The trend assessment was applied for the semi-arid Konya Basin (Turkey), one of the largest endorheic basins in the world. The results revealed a consistent increasing trend of both yearly evapotranspiration (totally 63 MCM yr−1 from croplands) and mean NDVI (about 0.004 NDVI yr−1 in irrigated croplands), especially concentrating in the plain part of the basin, while no significant trends were observed for the precipitation and potential evapotranspiration variables. On the contrary, a consistent decreasing trend of both yearly evapotranspiration (totally −2.1 MCM yr−1) and mean NDVI (−0.001 NDVI yr−1) was observed in the wetlands, which also cannot be explained by trends in precipitation and potential evapotranspiration. The emerging picture suggest that the greening trend of the vegetation and increasing of evapotranspiration in the plain are related to land cover changes (i.e. conversion into irrigated croplands) and to the intensification of the supplementary irrigation for agriculture, which in turn caused drying out of some wetlands and the natural vegetation which mostly depend on the groundwater, the main source of irrigation water as well. Our study presented an example of the utility of spatially and temporally continuous RS data in assessing the regional trends in hydrological and ecological variables and their interactions in a spatially distributed manner in a semi-arid region, which can also be adapted to other regions. Such spatiotemporally distributed analysis at the basin level is particularly important considering that most of the water management interventions also take place at this scale.