Uranium (U) in rocks and soils of arid and semi-arid environments can be mobilized by irrigation and fertilization, posing environmental and health risks. Elevated U, along with selenium (Se) and nitrate (NO₃) co-constituents, necessitates careful monitoring and management. We developed a distributed-parameter numerical model to assess U pollution in an irrigated stream-aquifer system, applying it to a 552 km² region in Colorado's Lower Arkansas River Valley (LARV) over 14 years. A MODFLOW model, describing groundwater and stream flow, was coupled with an RT3D-OTIS model to portray reactive U transport. Calibration using the PESTPP-iES iterative ensemble smoother (iES) software indicated good agreement with observed U concentrations. The model revealed substantial and variable U levels across the LARV, highlighting potential hotspots and possible contributing factors, such as geological composition of the bedrock and near-surface shale and aquifer sediments derived from them, irrigation practices, and riparian landscape. U levels exceed the chronic standard (85th percentile = 30 μg/L, set by the US Environmental Protection Agency), which is the permissible regulatory threshold, in groundwater across 44 % of the region and along the river by an average factor of 2.9. Simulated average U concentrations in the non-riparian aquifer and river are 124 μg/L and 60 μg/L, respectively, compared with 112 μg/L and 62 μg/L for measured values. The average 85th percentile U concentration is 222 μg/L in the aquifer and 82 μg/L in the river. Average simulated U mass loading to the river is 0.17 kg/day per km, compared to an estimated 0.23 kg/day per km. Findings provide a baseline for comparing future simulated outcomes of alternative best management practices (BMPs) for U pollution mitigation and offer a methodology applicable to other irrigated regions.