Detrital-zircon U-Pb geochronology documents a regional- to continental-scale drainage reorganization along the eastern Gulf Coastal Plain (USA) from the Late Cretaceous (Cenomanian) to the Paleocene–Eocene. We present detrital-zircon U-Pb ages and Th/U values from the Maastrichtian Ripley Formation to determine the sedimentary provenance and to provide spatiotemporal resolution of drainage reorganization. The Ripley Formation contains a 12.7% overall average abundance of detrital zircons with low (< 0.1) Th/U values relative to the underlying Cenomanian Tuscaloosa Group (3.6%), the overlying Paleocene–Eocene Wilcox Group (2.8%), an Appalachian foreland composite (2.1%), and the laterally equivalent McNairy Sandstone in the northern Mississippi Embayment (3.8%). Multidimensional scaling of detrital-zircon U-Pb spectra shows that the Ripley Formation is dissimilar from underlying and overlying Gulf Coastal Plain units, the McNairy Sandstone, and an Appalachian foreland composite sample because of differences in proportions of Appalachian (490–270 Ma) and Grenville (1250–900 Ma) zircons. We interpret the southern Appalachian Piedmont province as the principal sediment source region for the Ripley Formation to account for the elevated abundance of grains with low (< 0.1) Th/U values and unique detrital-zircon U-Pb age spectra. Results suggest a regional-scale (105 km2) drainage network, which delivered sediment to the Maastrichtian coast followed by northwestward littoral transport and eventual mixing with Appalachian foreland-derived sediment in the northern Mississippi Embayment. This study further brackets drainage reorganization along the eastern Gulf Coastal Plain and demonstrates how simple chemical–age relationships, such as zircon Th/U values coupled with U-Pb ages, can be used to evaluate sediment provenance.