The Maastrichtian–Cenozoic southern Middle Magdalena Valley Basin of Colombia contains a unique record of unconformities, strata, and structure, from which we extract the histories of exhumation of the Central Cordillera, to the west, and evolution of the Eastern Cordillera fold-and-thrust belt, to the east. This study integrates field-based analyses of stratigraphy, laboratory analyses of provenance, fission-track thermochronology, vitrinite-reflectance data, volcanic-ash geochronology, and studies of synorogenic geometries and structure displayed in seismic data. A major unconformity, the Middle Magdalena Valley unconformity, formed by eastward migration of Central Cordillera uplift during Late Cretaceous to early Eocene time, which transformed a Maastrichtian marine basin into a Paleocene depositional piedmont area. This transformation is recorded by a coarsening-upward sequence of marine shales to alluvial-fan conglomerates, which was partly eroded during further early Eocene propagation of Central Cordillera deformation. Cessation of this phase of uplift led to formation of a pediment surface, the Middle Magdalena Valley unconformity, which was buried by westward-onlapping middle Eocene to Neogene alluvial deposits. Middle Eocene to Neogene facies, paleoflow, and unconformities were controlled by Eastern Cordillera deformation. In the Eastern Cordillera foothills, growth strata and thermal history reveal two phases of folding of middle Eocene–Oligocene and late Miocene ages, prior to intense Pliocene–Pleistocene uplift. Two unconformities of early late Miocene and Pliocene–Pleistocene ages occur to the west of the Eastern Cordillera and record flexural tilting related to episodes of Eastern Cordillera loading.