In this study, HSPF (Hydrologic Simulation Program-FORTRAN) was used to analyze the potential impact of climate change on the streamflow of four major river basins in Ethiopia: Awash, Baro, Genale, and Tekeze. The calibrated and validated HSPF model was forced with daily climate data of 10 CMIP5 (Coupled Model Intercomparison Project phase 5) Global Climate Models (GCMs) for the 1971–2000 control period and the RCP4.5 and RCP8.5 climate projections of 2041–2070 (2050s) and 2071–2100 (2080s). The ensemble median of these 10 GCMs projects the temperature in the four study areas to increase by about 2.3 °C (3.3 °C) in 2050s (2080s), whereas the mean annual precipitation is projected to increase by about 6% (9%) in 2050s (2080s). This results in about 3% (6%) increase in the projected annual streamflow in Awash, Baro, and Tekeze rivers whereas the annual streamflow of Genale river is projected to increase by about 18% (33%) in the 2050s (2080s). However, such projected increase in the mean annual streamflow due to increasing precipitation over Ethiopia contradicts the decreasing trends in mean annual precipitation observed in recent decades. Regional climate models of high resolutions could provide more realistic climate projections for Ethiopia’s complex topography, thus reducing the uncertainties in future streamflow projections.