Topography-driven flow is normally considered to be the dominant groundwater flow system in uplifted sedimentary basins. In the U.S. midcontinent region east of the Rocky Mountains, the presence of brines derived from dissolution of halite suggests that significant topography-driven flushing has occurred to remove older brines that presumably formed concurrently with Permian evaporites in the basin. However, the presence of evaporites and brines in the modern basin suggests that buoyancy-driven flow could limit topography-driven flushing significantly. Here we used numerical models of variable-density fluid flow, halite dissolution, solute transport, and heat transport to quantify flow patterns and brine migration. Results indicate the coexistence of large-scale topography- and buoyancy-driven flow. Buoyancy-driven flow and low permeability evaporites act to isolate brines, and the residence time of the brines was found to be quite long, at least 50 Myr. The modern distribution of salinity appears to reflect near-steady-state conditions. Results suggest that flushing of original evaporatively-concentrated brines occurred tens of millions of years ago, possibly concurrent with maximum uplift ca. 60 Ma. Simulations also suggest that buoyancy-driven convection could drive chemical exchange with crystalline basement rocks, which could supply significant Ca2+, Sr2+, and metals to brines.