<p>Monitoring and evaluating groundwater resources is crucial as the rapid pollution challenges confronting surface water resources intensify. Failing to do so could have an adverse impact on various sectors of a nation’s economy. In this study, the groundwater quality of communities within the vicinities of the Volta Lake and Akosombo Dam in Ghana was comprehensively assessed for drinking and irrigation using multi-methodological approach. Standard experimental procedures were followed in the analysis of 107 groundwater samples. The samples showed hydrochemical concentrations in the order: TDS &gt; HCO₃^– &gt; Na⁺ &gt; SO₄^2– &gt; Mg²⁺ &gt; Cl^– &gt; K⁺ &gt; NO₃^– &gt; CO₃^2– &gt; F^–. The pH values were alkaline (&gt; 7.0), indicating ionized groundwaters. A&#xa0;high F^– concentration (3.8&#xa0;mg/l) was observed in one sample. Most had acceptable NO₃^– levels (&lt; 50 mg/l), except in four locations with levels &gt; 80 mg/l, which could lead to chronic diseases. Overall index of pollution (OIP) ranged from 0.10 to 0.92, indicating excellent drinking water. Contrarily, the groundwater samples were categorized as excellent (48.50%), good (49.53%), and poor (1.87%) by the water quality index (WQI). The OIP and WQI consistently ranked the groundwater suitability and their spatial maps showed fewer desirable sources in the western part, while the southeastern part had the best quality water. Groundwater mineralization was influenced by natural processes and human activities, per multivariate statistical analysis. Most irrigation water quality indices indicated unsuitability of majority of groundwater stations for irrigation. For both drinking and irrigation water quality predictions, multilinear regression and artificial neural network models performed well with low model errors and R² &gt; 0.90. It was indicated that Na⁺ had a major influence on the irrigation water quality prediction. These findings have significant implications for groundwater monitoring and protection, in the region and beyond.</p>