We determined U-Pb ages for detrital zircons from 26 samples of Paleozoic sandstone from the Grand Canyon. Cambrian strata yield mainly ca. 1.44 and 1.7–1.8 Ga ages that indicate derivation from nearby basement rocks of the Yavapai Province. Devonian strata contain zircons of 1.6–1.8 Ga, 1.34–1.40 Ga, and ca. 520 Ma, suggesting derivation from the Mazatzal and Yavapai Provinces, midcontinent region, and the Amarillo-Wichita uplift, respectively. Mississippian strata record a major change in provenance, with predominantly 415–475 Ma and 1030–1190 Ma grains interpreted to have been shed from the central Appalachian orogen. Pennsylvanian strata contain subequal proportions of 1.4–1.8 Ga grains derived from basement rocks exposed in the Ancestral Rocky Mountains and 409–464 and ca. 1070 Ma grains derived from the Appalachians. Permian strata contain abundant Appalachian zircons, including 270–380 Ma grains, and a lesser proportion of grains derived from the Ancestral Rocky Mountains. Transcontinental transport during Mississippian through Permian time is interpreted to have occurred in large river systems, facilitated by northeasterly trade winds during low sea level and by coastal currents. A compilation of young ages from all Upper Paleozoic strata yields age peaks of 270–365 Ma, 395–475 Ma, and 515–640 Ma, an excellent match for Alleghanian, Acadian, Taconic, and Neoproterozoic (peri-Gondwanan) episodes of magmatism along the Appalachian margin. Lag times of the youngest grains in these Upper Paleozoic strata average ∼25 m.y., suggesting relatively rapid exhumation and erosion of Appalachian source regions.