Sedimentary, hydrologic, and geochemical variations in the Hanford subsurface environment, as well as compositional differences in contaminating waste streams, have created vast differences in the migration and mobility of U within the subsurface environment. A series of hydraulically saturated and unsaturated column experiments were performed to (i) assess the effect of water content on the advective desorption and migration of U from contaminated sediments and (ii) evaluate the U concentration that can develop in pore water and/or groundwater as a result of desorption/dissolution reactions. Flow rate and moisture content were varied to evaluate the influence of contact time, pore water velocity, and macropore desaturation on aqueous U concentrations. Sediments were collected from the T-TX-TY tank farm complex and the 300 Area Process Ponds located on the Hanford Site, southeastern Washington State. The sediments vary in depth, mineralogy, and in contamination events. Experiments were conducted under mildly alkaline/calcareous conditions representative of conditions commonly encountered at repository sites across the arid western United States and, in particular, the Hanford site. Results illustrate the release of U from these sediments is kinetically controlled, and low water contents encountered within the Hanford vadose zone result in the formation of mobile–immobile water regimes, which isolate a fraction of the reactive sites within the sediments, effectively reducing the concentration of U released into migrating pore waters.