Mercury (Hg) burdens in top-predator fish differ substantially between adjacent South Carolina Coastal Plain river basins with similar wetlands coverage. In the Congaree River, floodwaters frequently originate in the Blue Ridge and Piedmont regions, where wetlands coverage and surface water dissolved methylmercury (MeHg) concentrations are low. Piedmont-driven flood events can lead to downward hydraulic gradients in the Coastal Plain riparian wetland margins, inhibiting MeHg transport from wetland sediments, and decreasing MeHg availability in the Congaree River habitat. In the adjacent Edisto River basin, floodwaters originate only within Coastal Plain sediments, maintaining upward hydraulic gradients even during flood events, promoting MeHg transport to the water column, and enhancing MeHg availability in the Edisto River habitat. These results indicate that flood hydrodynamics contribute to the variability in Hg vulnerability between Coastal Plain rivers and that comprehensive regional assessment of the relationship between flood hydrodynamics and Hg risk in Coastal Plain streams is warranted.