Arsenic enrichment in groundwater resources in deltas and floodplains of large sediment-rich rivers is a worldwide natural hazard to human health. High spatial variability of arsenic concentrations in affected river basins limits cost-effective mitigation strategies. Linking the chemical composition of groundwater with the topography and fluvial geomorphology is a promising approach for predicting arsenic pollution on a regional scale. Here we correlate the distribution of arsenic contaminated wells with the fluvial dynamics in the Amazon basin. Groundwater was sampled from tube wells along the Amazon River and its main tributaries in three distinct regions in Peru and Brazil. For each sample, the major and trace element concentrations were analyzed, and the position of the well within the sedimentary structure was determined. The results show that aquifers in poorly weathered sediments deposited by sediment-rich rivers are prone to mobilization and accumulation of aqueous arsenic and manganese, both in sub-Andean foreland basins, and in floodplains downstream. Two zones at risk are distinguished: aquifers in the channel-dominated part of the floodplain (CDF) and aquifers in the overbank deposits on the less-dynamic part of the floodplain (LDF). Some 70 % of the wells located on the CDF and 20 % on the LDF tap groundwater at concentrations exceeding the WHO guideline of 10 μg/L arsenic (max. 430 μg/L), and 70 % (CDF) and 50 % (LDF) exceeded 0.4 mg/L manganese (max. 6.6 mg/L). None of the water samples located outside the actual floodplain of sediment-rich rivers, or on riverbanks of sediment-poor rivers exceed 5 μg/L As, and only 4 % exceeded 0.4 mg/L Mn. The areas of highest risk can be delineated using satellite imagery. We observe similar patterns as in affected river basins in South and Southeast Asia indicating a key role of sedimentation processes and fluvial geomorphology in priming arsenic and manganese contamination in aquifers.