Background Fluorosis is endemic in many countries of Asia, South America, and Africa. In Africa, the countries located across the Great East African Rift Valley, including Ethiopia are a hotspot for fluorosis. While excessive and chronic exposure to fluoride causes dental and skeletal fluorosis, emerging studies have shown its adverse health effects in cognition, memory, learning and the function of central nervous system. The aim of this study is to assess neurological features of populations chronically exposed to a wide range of fluoride concentrations in drinking water wells in the Ethiopian Rift Valley.Method We conducted a study on 318 individuals living in rural villages located in fluoride endemic areas of the Ethiopian Rift Valley. Drinking water samples were collected from 23 community well sites, and analyzed for fluoride concentrations. Detailed clinical evaluations of skeletal fluorosis, neurologic history, and physical examination were performed in the study participants. Association between different fluoride concentrations and clinical features of fluorosis were done using chi square and crude odds ratio (OR).Results The mean age of the study participants was 28.0±14.9 years. Male accounted 55.7% of the subjects participated. About 80% of the participants were from the communities who used water from wells containing fluoride concentration >2 mg/L. The mean fluoride concentration in drinking water samples was 6.8±4.3 mg/L (range: 0.3 to 15.5 mg/L). Among the neurologic complications, headache, fatigue, and paresthesia accounted for 67%, 56.3%, and 37.5%, respectively. Impaired lumbar mobility, impaired squatting, impaired neck mobility, and knocked knee occurred in 22.3%, 6.6%, 2.2%, and 1.6%, respectively. Impaired lumbar mobility and kyphosis showed statistically significant association with higher fluoride concentration in drinking water (>2 mg/L) (P <0.05), while impaired squatting did not (p = 0.9) as compared to baseline fluoride concentration < 2mg/L.Conclusion Our findings strongly suggest that the adverse neurological and medical effects associated with prolonged exposure to elevated concentrations of fluoride in drinking water. We recommend conducting large scale epidemiological study in fluoride endemic areas using controlled population to better understand non-skeletal fluorosis related to neurological and medical complications.