In arid and semi-arid areas, human health and economic development depend on water availability, which can be greatly compromised by droughts. In some cases, the presence of natural contaminants may additionally reduce the availability of good quality water. This research analyzed the water resources and hydrochemical characteristics in a rural area of the central Main Ethiopian Rift Valley, particularly in the districts of Shashemene, Arsi Negelle, and Siraro. The study was developed using a census of the main water points (springs and wells) in the area and the sampling and physico-chemical analysis of the water, with particular regard to the fluoride concentration. In many cases, fluoride content exceeded the drinking water limits set by the World Health Organization, even in the absence of anthropogenic contamination. Two different aquifers were recognized: A shallow aquifer related to the eastern escarpment and highlands, and a deep aquifer in the lowland areas of the rift valley on the basis of compositional changes from Ca–Mg/HCO3 to Na–HCO3. The distribution of fluoride, as well as pH and EC values, showed a decrease from the center of the lowlands to the eastern highlands, with similar values closely aligned along an NNE/SSW trend. All these data contribute to creating awareness among and sharing information on the risks with rural communities and local governments to support the adequate use of the available water resources and to plan appropriate interventions to increase access to fresh water, aimed at the sustainable human and rural local development of the region.