Most people in Ghana have no or only basic access to safely managed water. Especially in rural areas, much of the population relies on groundwater for drinking, which can be contaminated with fluoride and lead to dental fluorosis. Children under the age of two are particularly susceptible to the adverse effects of fluoride and can retain 80–90% of a fluoride dose, compared to 60% in adults. Despite numerous local studies, no spatially continuous picture exists of the fluoride contamination across Ghana, nor is there any estimate of what proportion of the population is potentially exposed to unsafe fluoride levels. Here, we spatially model the probability of fluoride concentrations exceeding 1.0 mg/L in groundwater across Ghana to identify risk areas and estimate the number of children and adults exposed to unsafe fluoride levels in drinking water. We use a set of geospatial predictor variables with random forest modeling and evaluate the model performance through spatial cross-validation. We found that approximately 15% of the area of Ghana, mainly in the northeast, has a high probability of fluoride contamination. The total at-risk population is about 920,000 persons, or 3% of the population, with an estimated 240,000 children (0–9 years) in at-risk areas. In some districts, such as Karaga, Gushiegu, Tamale and Mion, 4 out of 10 children are potentially exposed to fluoride poisoning. Geology and high evapotranspiration are the main drivers of fluoride enrichment in groundwater. Consequently, climate change might put even greater pressure on the area’s water resources. Our hazard maps should raise awareness and understanding of geogenic fluoride contamination in Ghana and can advise decision making at local levels to avoid or mitigate fluoride-related risks.