Many alluvial aquifer systems are characterized in part by groundwater rich in sodium (Na) and bicarbonate (HCO3) and elevated concentrations of dissolved iron (Fe) and arsenic (As). However the relationships among Fe and As concentrations and the formation of Na-HCO3 waters are unclear. Here we evaluated the formation of Na-HCO3 groundwater in the Lower Mississippi River Alluvial Aquifer (LMRAA) in Louisiana, USA, where concentrations of dissolved Fe and As reached values as high as 16 mg/L and 64 μg/L, respectively. Water isotope data showed that groundwater was predominantly recharged via local precipitation outboard of the Mississippi River, while groundwater nearer the river and to the south of the study area was more hydraulically connected to the river. Much of the geochemical data, including water isotopes, calcite saturation index, Na excess, and As correlated to some degree with well depth, highlighting the complex interactions between the shallower recharge from local precipitation and the deeper reaction pathways laterally connected to the Mississippi River and/or vertically connected with regional groundwater. The δ13C(DIC) of groundwater ranged from -17.4 to -11.1‰ likely representing a mixture of microbially- and abiotically-derived alkalinity. Within this context, the production of groundwater rich in Na-HCO3 can be explained by reaction pathways involving the weathering of Ca-Na silicate phases. This weathering, driven in part by the production of microbial CO2 during Fe and sulfate reduction, may continue past the point of calcite saturation. Once calcite reaches saturation the concentration of Ca is buffered, but there is a possibility of further buildup in the concentrations of Na and HCO3. The silicate weathering model serves as an alternative conceptual model to calcite dissolution and clay exchange for the development of Na-HCO3 waters. If globally important, this water-rock reaction pathway could place new constraints on the processes influencing the fate and transport of Fe and As in alluvial aquifer systems.