The current study objective is to identify the hydro-geochemical processes and their relation with the groundwater quality in Safaga-El Quseir District, Egypt. The study approach includes conventional graphical plots and geochemical modeling of the hydrochemical data to define the evaluation of aquifer systems based on the ionic constituents, hydrochemical facies, and physiochemical processes controlling groundwater quality. The results suggest that different natural hydrogeochemical processes like simple dissolution, mixing, evaporation, weathering of carbonate minerals, silicate, and sulfate as well as ion exchange are the key factors controlling the groundwater quality at Safaga-El Quseir District. The results of geochemical modeling simulation show that the processes of evaporation, mixing, and water–rock interactions are the most effective processes governing the groundwater quality (composition) in study area. The mixing ratio of 90:10 (rain/Nubian) with evaporation of 90% gives a similar composition to Miocene groundwater, while a mixing ratio of 80:20 (rain/ Nubian) with evaporation of 90% lead to a composition similar to the Oligocene groundwater. As the contribution from the Nubian water component increase (becomes 50% or more), the simulation of mixing accompanied with evaporation of 90% gives a similar composition to both of the Alluvium and fractured basement aquifers which contain more mineralized water. The simulation of mixing in combination with evaporation gives results more comparable with the final compositions of the different samples collected from the study area than the simulation of evaporation alone. This is because both of evaporation and mixing have some bearings on the groundwater quality in Safaga-El Quseir District. The geochemical modeling results of the current study can be applied on similar localities along the Red Sea Coast in Egypt and Sudan.