The geological history of the Amazon River is a complex story driven by geodynamic processes operating in the South American plate. In spite of recent research, the pre-Neogene structure of Amazon paleodrainage is still underconstrained. A recent study has suggested that the western Amazonian paleodrainage system was reversed, cratonic in origin during the Cretaceous. However, the extent and duration of this system are not well-constrained. To add new constraints, we investigated the sources of Cretaceous sedimentary rocks in the Brazilian Acre and Peruvian Madre de Dios basins, based on major and trace element concentrations, Sm–Nd isotopic compositions, and U–Pb detrital zircon dating. The late Cretaceous samples of the Acre Basin have εNd(0) values between −21.2 and −8.4 and zircon grains derived from terranes situated in the easternmost part of the Amazonian Craton: Ventuari–Tapajos (2.0–1.82 Ga) and Rio Negro–Juruena (1.82–1.54 Ga). In contrast, the Madre de Dios Basin samples have εNd(0) values ranging from −15.2 to −7.1 and a wide range of U–Pb zircon age distributions. The samples from the northern part of the basin (MD234 and MD238) are dominated by zircon ages between 0.9 and 1.3 Ga (Grenville/Sunsás, 30 %–43 %) and 0.5 and 0.7 Ga (Brazilian/Pampean, 26 %–16 %) with felsic provenance. The oldest MD234 sample also shows a dominant contribution from Paleozoic zircon (20 %). On the other hand, the samples from the southern part of the Madre de Dios Basin (samples MD-2019-4A; MD-2019-10; MD-2019-13; MD-2019-11D and MD-2019-12A) have U–Pb age distributions dominated by zircon ages between 0.9 and 1.3 Ga (Grenville/Sunsás, 30 %–45 %) and 1.54 and 1.3 Ga (Rondonia–San Ignácio, 16 %–43 %), pointing to a cratonic origin for these sedimentary rocks. To elucidate the distinction in provenance between the samples from the northern and southern parts of the Madre de Dios Basin, we suggest that a structural barrier (the Madidi Arch (?)) was active during the late Cretaceous. In this scenario, the northern part of the Madre de Dios Basin had similar sedimentary sources as the nearby basins like Huallaga, Bagua, Ucayali, and Marañón, whereas, in the southern part of the basin, sedimentation was influenced by local sources. Together with previously published studies, these data indicate that the continent-wide cratonic drainage developed between the Cenomanian and Maastrichtian in response to the Purus Arch uplift was probably driven by a geodynamic process related to the post-rift opening of the Atlantic Equatorial Ocean.