The hydrochemistry of groundwater from the Mogher Al Mer area, located in southwestern Syria, has been used as a tool to identify and assess the hydrogeological systems and associated conditions. In this arid region of Syria, groundwater is considered as the main source of water supply for both drinking and irrigation purposes. The detailed description of hydrogeochemical conditions, including major ions, physico-chemical and in situ field parameters, has underlined the very complex variability of the stratigraphic sequences and hence the numerous hydrogeological units within the study area. On the one hand, groundwater chemical signature is found to be mainly controlled by the water–rock interaction processes in the mountainous western part of the study area. On the other hand, anthropogenic influences are observed in the eastern plain. In terms of recharge mechanisms, the region can be considered as a part of a main intermediate or even regional flow system instead of a local one.