Abstract: Groundwater overexploitation has resulted in huge scarcity and increase in the demand for water and food security in India. Groundwater in India has been observed to have experienced various water quality issues like arsenic, fluoride, and Uranium (U) contamination, leading to risk in human health. Markedly, the health risk of higher U in drinking water, as well as its chemical toxicity in groundwater have adverse effects on human. This study has reported occurrence of U as an emerging and widespread phenomenon in South Indian groundwater. Data on U in groundwater were generated from 284 samples along the Cretaceous Tertiary boundary within 4 seasons viz. pre-monsoon (PRM), southwest monsoon (SWM), northeast monsoon (NEM), and post-monsoon (POM). High U concentrations (74 μgL−1) showed to be above the World Health Organization’s provisional guideline value of 30 μgL−1. The geochemical, stable isotope and geophysical studies suggested that U in groundwater could vary with respect to season and was noted to be highest during NEM. The bicarbonate (HCO3) released by weathering process during monsoon could affect the saturation index (SI)Calcite and carbonate species of U. However, the primary source of U was found to be due to geogenic factors, like weathering, dissolution, and groundwater level fluctuation, and that, U mobilization could be enhanced due to anthropogenic activities. The findings further indicated that groundwater in the study area has reached the alarming stage of chemical toxicity. Hence, it is urgent and imperative that workable management strategies for sustainable drinking water source be developed and preventive measures be undertaken, relative to these water quality concerns to mitigate their disconcerting effect on human health.