The rise of the Andes and the associated propagation of the retroarc foreland basin during the Mesozoic Cenozoic in western South America shaped the paleogeography and paleoenvironmental settings of Western Amazonia. Much attention has been paid to the Neogene evolution of the Amazonian Basin, but few studies have investigated in detail the paleoenvironments of Western Amazonia during the Paleogene. We present a multi-proxy study that includes new biostratigraphic and paleontologic data, the interpretation of depositional environments and zircon U–Pb data from the Upper Cretaceous-Paleogene sedimentary sequence exposed in the Huallaga Basin (northern Peru). The biostratigraphic dating suggests that the lower part of the sequence is Maastrichtian in age. The maximum depositional age and maximum likelihood age according to the U–Pb zircon dating of Paleogene sedimentary rocks indicate Lutetian to Bartonian ages (from 43.5 ± 0.64 Ma to 37.6 ± 0.85 Ma). These results reveal a hiatus in the depositional record during Paleocene time. Two depositional systems can be distinguished: a lacustrine system composed of red mudrocks interbedded with thick sandstone layers and carbonate beds, and a siliciclastic tide-dominated system composed of fine-to medium-grained sandstones associated with tidal bundles, reactivation surfaces and heterolithic stratifications. However, the carbon and oxygen stable isotope values in carbonates tend to characterize a freshwater system, with a transition to brackish conditions toward the upper part of the section (Bartonian), thereby suggesting the presence of an estuary system. Finally, we suggest that the Bartonian shallow marine incursion recorded in the Huallaga Basin occurred from the north through the Caribbean Sea, and that it might have played a role in regional biodiversity patterns in the Paleogene.