The Colorado River in the SW of the USA is one of Earth’s few continental-scale rivers with an active margin delta. Deformation along this transform margin, as well as associated intra-plate strain, has resulted in significant changes in sediment routing from the continental interior and post-depositional translation of older deltaic units. The oldest candidate deposits, fluvial sandstones of the Eocene Sespe Group, are now exposed in the Santa Monica Mountains, 300 km to the north of the Colorado River. Heavy mineral data from this basin indicate that sediment was sourced by a large river system, with some affinity to the early Pliocene Colorado River, but was unlikely to have been integrated across the Colorado Plateau. Sedimentological and mineralogical evidence from the earliest (c. 5.3 Ma) unequivocal Colorado River-derived sediments in the Salton Trough provide evidence for a rapid transition from locally derived sedimentation. Lack of evidence for a precursor phase of suspended-load sediment suggests that drainage capture took place in a proximal position, favouring a ‘top-down’ process of lake spillover. Following drainage integration, significant changes in heavy mineral assemblages of fluvio-deltaic sediments, particularly evident from apatite–tourmaline and garnet–zir-con indices, as well as U–Pb ages of detrital zircons, document the integration of the fluvial system to its present form and progressive incision of the Colorado Plateau from the Miocene to the present.