To understand groundwater pollution and its associated health hazards and to ensure the availability of a clean, safe, and sustainable water supply, comprehensive research plays a crucial role. This article presents an integrated investigation of groundwater conditions, hydrogeochemistry, and health implications arising from fluoride (F⁻) and nitrate (NO₃⁻) contamination in eastern Ghana. Analysis of 107 samples revealed variable groundwater suitability for human consumption, as indicated by Pollution Index of Groundwater (PIG) values ranging from 0.11 to 1.19. The study highlights significant variations in health hazard risks due to F⁻ and NO₃⁻ exposure. Hazard indices (HIs) for nitrate ingestion range from 0.000 to 16.321, for fluoride ingestion from 0.000 to 17.426, and for the combined ingestion risks from 0.000 to 17.602. Dermal absorption risk for nitrate is minimal, with values between 0.000 and 0.049. Spatially distinct contamination and health risks are mapped using GIS, pinpointing vulnerable localities in the study region. Hydrochemical investigations, confirmed by clustering and factor analyses, revealed that natural geological processes are the primary drivers of groundwater quality and mineralization, with limited anthropogenic impacts. Further, an artificial neural network model with an impressive R2 of 0.976 and low statistical errors demonstrated strong potential for accurate prediction of groundwater quality. The holistic study approach significantly advances groundwater research in the region, paving the way for effective resource management strategies by revealing areas of concern, understanding the contamination drivers, and predicting future water quality with high accuracy.