Sustainable management of water for human uses and maintaining river health requires reliable information about the future availability of water resources. We quantified the separate and combined impacts of climate and land cover changes on runoff for the historical record and for modelled future scenarios in the upper Han River and Luan River, supply and demand zones respectively of the middle route of the South to North Water Transfer Project in China, the world’s largest inter-basin water transfer project. We used a precipitation-runoff model, averaged multiple climate model predictions combined with three emissions scenarios, a combined CA-Markov model to predict land cover change, and a range of statistical tests. Comparing baseline with 2050: climate change would cause an average reduction in runoff of up to 15 % in the upper Han River and up to 9 % in the Luan River catchment; a scenario involving increased forest cover would reduce runoff by up to 0.19 % in the upper Han River and up to 35 % in the Luan River; a scenario involving increased grass cover would increase runoff by up to 0.42 % in the upper Han River and up to 20 % in the Luan River. In the lower Luan River, the mean annual flow after 1998 fell to only 17 % of that of the baseline period, posing a serious threat to river health. This was explained largely by extraction of surface water and groundwater, rather than climate and land use change.