Brazilian electric power is mostly based on hydraulics sources through hydropower plant reservoirs that are fed by rivers located in Southeast Brazil. Possible changes in climate can affect the energy supply of the country. The objective of this work is to assess the possible changes in the hydrology of the Upper Grande River Basin (UGRB) under a future climate change scenario, using the Lavras Simulation of Hydrology (LASH) model forced by the outputs of the Eta model, a regional climate model, which was driven by HadCM3 A1B scenario for three time slices in the period between 2011 and 2099. Owing to the surface heterogeneity of the region, the hydrologic model was previously calibrated for four watersheds of the UGRB, which are located in its headwater region and evaluated against observational time series of the present climate period, 1961–1990. In the first future time slice, 2011–2040, the results showed a small reduction in the annual run-off, but for the other time slices, the trend changed to strong increase in most of the watersheds. The water budget in the region calculated from the Eta model agreed with the run-off trends, as water excess reduced in the first time slice and gradually increased towards the end of the century. The run-off components showed intraseasonal variability. The reduction of rains in the end of winter, the dry period in the region, and in the beginning of spring, may cause a change in the dynamics of the groundwater recharge, affecting the base flow, which can extend and intensify the flow recession period, and therefore affect the availability of water resources. On the other hand, the increase of rains during the summer, the rainy season of the region, caused an increase of the direct surface run-off, which can modify the flood regimes of the rivers in the region.