This study addresses multiple controls on foreland-basin accommodation and contributes to enhanced understanding of the evolution of the northern Andes. The Middle Magdalena Valley Basin (MMVB), Eastern Cordillera, and Llanos Basin are part of a Late Cretaceous–Cenozoic foreland-basin system, east of the Colombian Central Cordillera. Mechanical modeling indicates that the primary control on complex distributions of sedimentary thicknesses, facies, and unconformities was lithospheric flexure in response to crustal loads from the Central and Eastern Cordilleras. Shorter-wavelength folding and paleoaltitude determined the local character of strata. Our mechanical modeling consists of the application of orogenic and sedimentary loads extracted from geologic data on a continuous elastic lithosphere. The results validate two major basin configurations. The first configuration was a Maastrichtian–early Eocene foreland basin coupled with Central Cordillera uplift. Growth strata record continuous sedimentation in the Eastern Cordillera, whereas regional unconformities in the Llanos Basin (distal foreland basin) reflect isostatic adjustments of the basin's amplitude and wavelength to Central Cordillera episodic uplift and tectonic quiescence. The second major basin configuration was characterized by Central Cordillera erosion since middle Eocene times recorded by a regional pediment surface. In the absence of Central Cordillera effective loading, loads from onlapping sediments and Eastern Cordillera piggyback sub-basins provoked post–middle Eocene accommodation in the MMVB and Llanos Basin. Intensified Eastern Cordillera uplift during the Neogene produced basinal tilting recorded by unconformities in the MMVB. This study highlights the importance of assessing the causes of tectonic accommodation as a foundation for interpretation of the evolution of large foreland and intermontane basins.