Surface uplift of the Garzon Massif in the northern Andes formed a critical orographic barrier (2500–3000 m elevation) that generated a deep rain shadow and strongly influenced the evolution of the largest river systems draining northern South America. This basement massif and its corresponding foreland basement high define the headwaters and drainage divides of the Amazon, Orinoco, and Magdalena Rivers. Despite its pivotal role, the exhumation history of the Garzon Massif and its relationships to the structural evolution of the broader Eastern Cordillera fold-thrust belt remain unclear. The northern Andes underwent major Cenozoic shortening, with considerable thin-skinned and thick-skinned deformation and topographic development in the Eastern Cordillera focused during late Miocene time. On the basis of widespread coarse-grained nonmarine sedimentation, previous studies have inferred that uplift of the Garzon Massif began during the late Miocene, coincident with rapid elevation gain elsewhere in the Eastern Cordillera. We take an integrated, multiproxy approach to better reconstruct Andean topographic growth and distinguish between exhumation and surface uplift of the Garzon Massif. We present new U-Pb detrital zircon provenance data, sandstone petrographic data, and paleoprecipitation data from upper Miocene clastic fill of the Neiva Basin within the adjacent Upper Magdalena Valley of the modern hinterland. In addition, six new apatite fission track (AFT) ages from the central segment of the northeast-trending Garzon Massif (Jurassic granite and Proterozoic gneiss and schist) directly constrain its Neogene exhumation history. The results indicate that early exhumation may have initiated by ca. 12.5 Ma, but a substantial orographic barrier was not fully established until ca. 6–3 Ma, when >1 km/m.y. of material was exhumed. Thermal history modeling of the AFT data suggests diminished exhumation thereafter (3–0 Ma), during latest Cenozoic oblique Nazca–South America convergence. This exhumation history is consistent with paleontological data suggesting late Miocene divergence of the three river systems, with associated transcontinental drainage of the Amazon River.