Fluoride (F⁻) contamination in groundwater is a major challenge in many developing countries like Ghana. It is commonly observed that the heterogeneous nature of the geology plays a pivotal role in governing the fluoride mobilization in groundwater. Therefore, this study employed a multi-approach involving hydrogeochemistry and multivariate statistical analysis to investigate the geochemical controls on high F^- in the geologically heterogeneous Bongo District of Ghana. The study also assessed the probable human health risks associated with consuming F^- contaminated groundwater. The study revealed that the dominant water type identified in the area was Na-HCO3-Cl with other mixed water types. The F^- levels ranged from 0.43 to 3.61 mg/L (average: 1.89 mg/L). Five principal components with eigen values >1.0 explaining a total variance of 88.8% were obtained from factor analysis indicating that both geogenic and anthropogenic sources control the groundwater chemistry. However, F⁻ mobilization in groundwater is largely because of weathering, ion exchange reactions and dissolution of F^- bearing minerals found in the aquifers. Further, geochemical modelling indicates that the groundwater is undersaturated with respect to calcite, dolomite, fluorite, gypsum, anhydrite, aragonite, halite and quartz. The human health risk assessment showed that children had higher hazard quotient values (0.61–5.11), implying they are more prone to dental fluorosis than the other age groups. Therefore, it is recommended that artificial recharge along with sustainable defluoridation techniques such as absorption, electrodialysis and precipitation should be adopted to remediate the high fluoride menace. In addition, cost-effective and Ghanaian-friendly natural coagulants/absorbents like Moringa oleifera and bone char can be promoted for usage at the household level to reduce the fluoride levels in groundwater prior to domestic usage.