Numerical experiments were carried out to investigate the fluid flow in typical Proterozoic basins that host unconformity-related uranium deposits. We have constructed a simplified conceptual model by integrating important features shared by the Athabasca, Thelon, and Kombolgie Basins. Based on this conceptual model, various numerical scenarios were designed to explore the interaction between fluid flow, heat transport, topographic relief, and tectonic deformation. Our modeling suggests that thermally driven free convection may develop in the thick sandstone sequence at a geothermal gradient of between 25° and 35°C/km during periods of tectonic quiescence, with a maximum velocity of about 1.0 m/yr. However, reactivation of preexisting basement structures and the generation of new faults suppressed free convection and led to deformation-dominated fluid flow or mixed convection, depending on strain rates. During compressive deformation, reduced brines in the basement may flow out along fractured zones and encounter uranium-bearing fluids in the clastic sequence to form sandstone-hosted deposits. In contrast, basement-hosted deposits are likely to form during extension, when oxidized basinal brines flow into faulted structures to interact with reduced minerals or fluids in the basement. Maximum flow rates are estimated to be up to ~7 and ~2.5 m/yr in the relatively high permeability fracture zone for compressive and extensional deformation, respectively, given a strain rate of 10−13 s−1 and a geothermal gradient of 30°C/km. In addition, the rate of pressure accumulation and dissipation is different in various geologic units depending on their hydrological properties and strain rates.