Detrital zircons (DZ) from fluvial sandstones of the Western Canada Sedimentary Basin and the U.S. Gulf of Mexico (GoM) passive margin indicate mid-Cretaceous through Paleocene continental-scale drainage reorganization. DZ populations from the Early Cretaceous Mannville Group of Alberta represent a continental-scale system that routed sediment from the Appalachian Mountains and the eastern three-quarters of North America to the Boreal Sea. In contrast, DZ populations from the GoM coastal plain show that only the southern United States and Appalachian-Ouachita orogen contributed sediment to the GoM through the Late Cretaceous, whereas by the Paleocene, southern North America, from the Western Cordillera to the Appalachian Mountains, had been routed to the GoM. This continental-scale drainage reorganization reflects the culmination of an ∼300 m.y. trajectory that began with Paleozoic Appalachian assembly, and broad east to west sediment routing, followed by assembly of the Mesozoic Western Cordillera, which resulted in west-derived rivers in the United States draining to the GoM in Texas, or to an ancestral Mississippi River in the Mississippi embayment, setting up the template for sediment routing that persists today.