Reports have shown that potentially toxic elements (PTEs) in air, water, and soil systems expose humans to carcinogenic and non-carcinogenic health risks. In southeastern Nigeria, works that have used data-driven algorithms in predicting PTEs in groundwater are scarce. In addition, only a few works have simulated water quality indices using machine learning modelling methods in the region. Therefore, in this study, physicochemical analyses were carried out on groundwater samples in southeastern Nigeria. The laboratory results were used to compute two water quality indices: pollution index of groundwater (PIG) and the water pollution index (WPI), to ascertain groundwater quality. In addition, the physicochemical parameters served as input variables for multiple linear regression (MLR) and artificial neural network (ANN) modelling and prediction of Cr, Fe, Ni, NO
3
−
, Pb, Zn, WPI, and PIG. The results of WPI and PIG computation showed that about 30–35% of the groundwater samples were unsuitable for human consumption, whereas 65–70% of the samples were deemed suitable. The insights from the PIG and WPI model also revealed that lead (Pb) was the most influential PTE that degraded the quality of groundwater resources in the research area. The findings of the MLR and ANN models indicated strong positive prediction accuracies (
R
2
= 0.856–1.000) with low modeling errors. The predictive MLR and ANN models of the PIG and WPI generally outperformed those of the PTEs. The models produced in this study predicted the PTEs better compared to previous studies. Thus, this work provides insights into effective water sustainability, management, and protection.