<p>The justification for the need for continuous assessment and monitoring of groundwater (GW) quality lies in the global demand for safe, clean, accessible water for all. Earlier works in parts of the Wassa West District of Ghana, where the study area belongs, reported groundwater quality issues, justifying the need for further groundwater pollution investigation within the catchment. Indexical proxies and multivariate statistics have been used in pollution studies, however, a combination of multiple proxies, multivariate statistics, prediction modeling, and spatial mapping will elucidate comprehensively the pollution patterns of groundwater in the catchment. Hence, this study used multi-indexical proxies of water quality index (WQI), groundwater pollution index (GPI), water pollution index (WPI), percentage of pollution index (PPI), compositional pollution index (CPI), water nutrients pollution index (WNPI), and nitrogen pollution index (NPI) together with multivariate statistics, and multilinear regression modeling (MLM) to characterize and predict the groundwater pollution in the area. The physicochemical parameters, except for NO₃⁻, K⁺, and HCO₃⁻, in 8%, 2%, and 1% of the sample locations, respectively, were all within the World Health Organization (WHO) allowable limits. Also, 22% of samples had acidic groundwater. Although the WQI suggests 100% good GW in the area, GPI, WPI, and CPI indicated 100%, 100%, and 88% polluted GW, respectively. The multivariate analysis shows that GPI and CPI indicate geogenic pollution effects, while WPI, PPI, WNPI, and NPI reveal the negative effects of anthropogenic activities on the GW quality. The MLM for GPI and WPI yielded exceptional performance with R² values of 99% and 100%, and SEE values of 0.028 and 0.003, respectively. The study recommends the immediate monitoring and mitigation of the acidic aquifers within the catchment, so as to prevent future dental cavity issues in the area.</p>