The integration of sandstone petrography, detrital zircon U-Pb ages, and sedimentological data was carried out for lower Paleogene rocks in four sections of the western Maracaibo Block, allowing for the documentation of a shift from regional to localized fluvial drainage systems associated with intraplate uplifts. The lower to middle Paleocene units have similar thicknesses, and show a depositional profile varying northward from fluvial-estuarine environments to shallow marine carbonates. Sandstones show high quartz percentages (up to 80%) and detrital zircon age populations are dominantly older than 0.9 Ga (with peaks in 1.55 and 1.8 Ga), with minor populations in the range of 400–600 Ma. In contrast, the upper Paleocene units were deposited in marginal, coal-rich environments, and have strong variations in thickness among the four studied areas. These sandstones show quartz percentages between 40 and 70%, and have a significant increase in metamorphic fragments (approximately 13% of the total framework) as compared to the lower Paleocene sandstones (5–7% of metamorphic lithic fragments). The lower Eocene sandstones, on the other hand, show an increase in k-feldspars and quartz content. The detrital zircon age populations for the upper Paleocene and lower Eocene sandstones in the western sections show a strong decrease in ages from 1.3 to 2.5 Ga and an increase in ages from 55 to 360 Ma; in contrast, age populations older than 0.9 Ga persist in the southern section. The lower-middle Paleocene rocks suggest a regional, basin-wide drainage system fed by the Cretaceous sedimentary cover exposed in low-amplitude localized uplifts and developed a mixed siliciclastic-carbonatic platform in the shelf areas. On the other hand, the upper Paleocene-lower Eocene synorogenic succession accumulated in several basin compartments separated by more pronounced source areas and recorded the introduction of new ones. These sandstones contain basement rock fragments from marginal uplifts of the Santa Marta Massif and the Central Cordillera, as well as fragments from emerging intraplate ranges, such as the Perijá Range and the Santander massif. Caribbean subduction along the northwestern margin of South America induced tectonic changes inside the Maracaibo Block, modifing sedimentary depocenters from a regional basin (ca. 300 km width) to isolated intermontane basins, which have been separated since the late Paleocene to present.