Recently reported detrital zircon (DZ) data help to associate the Paleogene strata of the Gulf of Mexico region to various provenance areas. By far, recent work has emphasised upper Paleocene-lower Eocene and upper Oligocene strata that were deposited during the two episodes of the highest sediment supply in the Paleogene. The data reveal a dynamic drainage history, including (1) initial routing of western Cordilleran drainages towards the Gulf of Mexico in the Paleocene, (2) an eastward shift of the western continental divide, from the Jura-Cretaceous cordilleran arc to the eastern edge of the Laramide province after the Paleocene and (3) a southward shift, along the eastern Laramide province, of the headwaters of river systems draining to the Mississippi and Houston embayments at some time between the early Eocene and Oligocene. However, DZ characterisation of most (~20 Myr) of the middle Eocene-lower Oligocene section remains limited. We present 60 DZ age spectra, most of which are from the middle or upper Eocene outcrop belts, with 50–200-km spacing. We define six to eight distinct groups of DZ age spectra for middle and upper Eocene strata. Data from this and other studies resolve at least six substantial temporal changes in age spectra at various positions along the continental margin. The evolving age spectra constrain the middle and upper Eocene drainage patterns of large parts of interior North America. The most well-resolved aspects of these drainage patterns include (1) persistent rivers that flowed from erosional landscapes across the Paleozoic Appalachian orogen either into the low-lying Mississippi embayment or directly into the eastern Gulf; (2) at least during marine regressions, a trunk channel that likely flowed southward along the axial part of Mississippi Embayment and integrated tributaries from the east and west; and (3) rivers that flowed to the Houston embayment in the middle Eocene that likely originated in the Laramide province in central Colorado and southern Wyoming, as Precambrian basement highs in those source areas were being unroofed.