The climate change impacts on the Nile River water quality can be considered as one of the serious water resource management challenges in Egypt. Thus, this study highlights the climate change trends that affect the Nile water quality deterioration upstream of Cairo drinking water treatment plants (WTPs). However, input from Intergovernmental Panel Climate Change (IPCC) greenhouse emission climate data were assessed to determine the extreme future climate change impact scenarios on Nile flow. Consequently, Water Quality Analysis Simulation Program (WASP) was used to evaluate and predict the river hydrodynamics variation trends due to the climate change impacts. Two main water quality indices (WQIs) are involved in river water parameters are assessed to evaluate the current situation. Moreover, the study results revealed that future climate change has a noted effect on the water quality indices upstream Cairo drinking water treatment plants (WTPs). This affirms the need for many coordination and monitoring activities to verify the proper functioning of the waterways.