This study presents the first integrated geographic and predictive modeling assessment of Hofmeister ions in groundwater and their potential link to chronic kidney disease of unknown etiology (CKDu) in South Sinai, Egypt. A total of 25 groundwater samples were collected from Wadi Feiran and Wadi El Sheikh and analyzed for major ions, nutrients, and key physicochemical parameters. The results revealed alarmingly high levels of nitrate (mean = 478.1 ppm) and total dissolved solids (TDS, mean = 2093 ppm), far exceeding World Health Organization (WHO) safety standards, and pointing to substantial potential risks to public health in these arid communities. Although the weighted arithmetic Water Quality Index (WQI) classified all samples as “good” to “excellent,” detailed hydrochemical assessment showed that concentrations of Hofmeister ions—particularly calcium and sodium—surpassed safe average daily intake thresholds in many samples (21 and 16, respectively). Such exceedances raise concerns over the potential development of hypercalcemia, hypertension, and the progression of CKDu, particularly among populations with limited access to alternative drinking water sources. Hydrochemical interpretations suggest that rock–water interactions, evaporation, and anthropogenic inputs are likely contributors to the observed ion levels. Predictive modeling using multiple linear regression (MLR) demonstrated excellent performance (R² = 99.71 % for nitrate), highlighting its value in forecasting contamination trends and identifying groundwater vulnerability hotspots in data-scarce arid regions. These findings underscore the urgent need for targeted groundwater quality monitoring, the integration of predictive risk modeling into management frameworks, and the implementation of preventive public health measures. By bridging geochemical data with health risk metrics, this research provides a scientific basis for developing evidence-based policies to safeguard communities and promote the sustainable use of groundwater resources in arid environments.