Abstract Seismic reflection data from Vincennes Bay, East Antarctica, provide the first insights into the Cenozoic evolution of the East Antarctic Ice Sheet (EAIS) in the Knox Coast. Long‐distance seismic horizon correlation allows age estimates for the seismic stratigraphic framework constructed for the continental shelf. Preglacial depositional patterns reveal extensive fluvial plains on the continental shelf from the Late Cretaceous until the latest Eocene (∼34 Ma). These transitioned to glaciofluvial outwash plains during the late Oligocene. The earliest clear indication of ice sheets present on the Vincennes Bay continental shelf are two generations of large buried tunnel valley systems that developed during the Oligocene‐Miocene Transition (∼24 Ma) and early Miocene during meltwater‐rich glaciations originating in the Knox Coastal Plain. Glacially transported sediment wedges deposited at the end of the early mid‐Miocene (>∼14 Ma) mark the beginning of steep glacial progradation of the continental shelf continuing through the Miocene and Pliocene. Ice sheet development from the late mid‐Miocene to the Quaternary is likely driven by the Aurora Subglacial Basin via the Vanderford Glacier. This suggests a major reorganization of ice flow from the early glaciations of the Oligocene and early Miocene to the later development of modern configurations, established in the late mid‐Miocene. Our results provide the first data of the Cenozoic development of the EAIS in Vincennes Bay and demonstrate the variability of ice flow conditions with past climatic changes. Plain Language Summary The long‐term development of the East Antarctic Ice Sheet (EAIS) is recorded by glacially transported sediments on continental shelves. We use seismic reflection data in Vincennes Bay correlated to offshore drill sites to analyze the development of ice sheets in the region during the Cenozoic. During the Late Cretaceous to the Eocene (until ∼34 Ma) fluvial channel systems shaped the continental shelf, which changed to glacial braided channel systems in the late Oligocene. Between the late Oligocene and early Miocene (∼24 Ma) subglacial channel systems suggest the presence of a grounded ice sheet advancing from the western Knox Coast. From the late mid‐Miocene (>∼14 Ma) to the Quaternary an ice sheet likely flowed from the eastern Knox Coast, likely the Vanderford Glacier, which built up the continental shelf seawards. This suggests a change in general ice flow of the EAIS during the early Miocene to early mid‐Miocene potentially due to the influence of past climatic changes. Key Points Alpine‐like glaciers first established in Vincennes Bay during late Oligocene, replacing Late Cretaceous to Eocene rivers of alluvial plains Oligocene‐Miocene transition tunnel valley orientation suggest early to mid‐Miocene ice sheet reconfiguration to modern glacial dynamics Shelf progradation from late mid‐Miocene to Pleistocene extends Vincennes Bay shelf through repeated glacial advances to paleo‐shelf break