Development of the Colombian Middle Magdalena Valley Basin (MMVB) was determined by late Cretaceous-early Eocene uplift of the Central Cordillera to the west, and subsequent transferal of deformation to the Eastern Cordillera to the east. These phases are separated in the tectono-stratigraphic record by a major unconformity, the Middle Magdalena Valley unconformity (MMVU). Paleocene coastal to alluvial facies underneath the MMVU were deposited in a foreland basin coupled to Central Cordillera kilometer-scale uplift. The middle Eocene to Neogene continental strata that onlap the MMVU document transformation of the MMVB into an interior basin due to Eastern Cordillera deformation recorded by growth strata in seismic lines and changing provenance and paleoflow patterns. Exhumation histories of the MMVB bounding ranges are further constrained by apatit-fission-track and vitrinite reflectance thermochronology and volcanic ash chronology. This study indicates that the MMVB is fundamentally related to evolution of the entire Andean margin of South America.