The sources of the tremendous amount of Cenozoic siliciclastic sediment deposited in the Gulf of Mexico region remain debated because of a lack of definitive provenance-identifying characteristics. In an effort to build on prior provenance analysis, we present 101–160 single-grain detrital zircon U-Pb ages for each of 10 outcrop samples from Upper Paleocene to Upper Miocene sandstones from a ∼10,000 km2 swath of central Louisiana corresponding to the ancient Mississippi River Delta, the largest Cenozoic depocenter in the northern Gulf of Mexico region. Sample depositional age control is derived from biostratigraphy and/or regional lithostratigraphic correlation. U-Pb ages in each of the samples range from Cenozoic to Archean, and correspond to the ages of various geologic terranes that underlie the modern Mississippi River drainage basin. However, the prominence of various age distributions changes systematically through the Cenozoic stratigraphy, and pronounced shifts in the abundance of certain age distributions between stratal packages appear to be correlated to shifts in heavy mineral assemblages recorded across the northern Gulf of Mexico coastal plain. Comparison of coastal plain detrital zircon age distributions to age distributions from North American sedimentary cover and the ages of major North American crystalline basement rocks, aided by a sediment mixing model, illuminates the provenance of each of the stratal packages, and suggests that (1) the Mississippi River catchment has resembled its present configuration, at least in the east-west dimension, for much, if not all, of the Cenozoic, and (2) depositional episodes on the Louisiana coastal plain characterized by high sediment supply also corresponded to high proportions of sediment sourcing from the Sevier-Laramide region of the interior western United States. Sediment supply to the Louisiana coastal plain by the paleo–Mississippi River has generally been high during the Cenozoic, except for an anomalous low during the Middle Eocene, when the abundance of sediment derived from the Rocky Mountain region decreased dramatically relative to sediment derived from the Appalachian region.