The present work focuses on understanding the provenance, prevalence and health perspective of As and F− along with possible co-occurrence of uranium (U) in the aquifers of the Brahmaputra floodplains (BFP), India. Groundwater (n = 164) and sediment samples (n = 5) were obtained from the upper, middle and lower BFP. Energy dispersive spectroscopy (EDX) revealed the presence of As, U and Fe in the sediment matrix. Regression analysis showed a weaker relationship between As and F− co-occurrence. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) suggested reductive dissolution of Fe (hydr)oxides responsible for As release in the BFP, especially in the upper and lower BFP. Bicarbonate appeared to compete with As oxyanions for adsorption on positively charged surfaces leading to As release. Arsenic desorption in presence of PO43−, F− and HCO3− at elevated pH appeared greatest in the upper BFP, suggesting the highest potential for co-occurrence. Co-occurrence, were mainly in isolated aquifers of the upper BFP owing to desorption of adsorbed As and F− from Fe (hydr)oxides at higher pH. Weathering and dissolution of clay minerals in the upper BFP, and competitive desorption in presence of HCO3− and PO43− in the middle and lower BFP, respectively, explain variabilities in F− release. Amorphous Fe (hydr)oxides like ferrihydrite act as sinks of U. Concentrations of As and F− will likely increase in the future as projected from the saturated levels of goethite and ferrihydrite. Hazard indices (HI) revealed that children (3–8 years) were at greater health risk than adults.