Three-dimensional modeling that integrates fluvial sediment transport, crustal-scale tectonic deformation, and lithospheric flexural subsidence is carried out to simulate the landscape and drainage evolution of the Ebro sedimentary basin (NE Iberia). The Ebro Basin underwent a long period of closed intramountain drainage as a result of tectonic topography generation at the Pyrenees, the Iberian Range, and the Catalan Coastal Range. In the late Oligocene, the Catalan Coastal Range underwent extension leading to the formation of the Valencia Trough (NW Mediterranean), but the Ebro Basin remained closed for nearly 15 Myr more before the Ebro River cut through the remnants of the topographic barrier. This drainage opening caused widespread basin incision that shaped spectacular outcrops of the syntectonic and posttectonic infill. Here we investigate the processes controlling these major drainage changes. The modeling results, constrained by a large data set on the tectonic and transport evolution of the area, predict a closed phase characterized by a large lake in the central eastern Ebro Basin. Dry climatic conditions probably lowered the lake level and contributed, together with rift flank uplift, to prolong this endorheic basin stage. The age and amount of reworked sediment after the opening are consistent with an onset of basin incision between 13 and 8.5 Ma as a result of lake capture by escarpment erosion and lake level rise associated with sediment accumulation and wetter climatic conditions. Sea level changes in the Mediterranean had no major impact in the large-scale drainage evolution of the Ebro Basin.