Rocks exposed along both sides of the Smith Sound in Ellesmere Island and NW Greenland record the tectono-sedimentary evolution of the whole Phanerozoic, including two periods of mountain building—the Palaeozoic Ellesmerian Orogeny and the Palaeogene Eurekan Orogeny—and the formation of two major sedimentary basins, the Franklinian and the Sverdrup Basins. We used geo- and thermochronology and apatite chemistry data to unravel this evolution. Apatite fission track and (U-Th)/He dates vary strongly from >600 to <100 Ma. We present internally consistent thermal history models, which allow to explain the data variations by a unitized exhumation and burial history. Our models suggest that the cratonic areas were buried beneath a several km-thick succession of Franklinian Basin deposits. During the Ellesmerian Orogeny, the craton acted as sediment source, as also suggested by the composition of apatite and by U-Pb ages of zircon contained in Devonian foreland sediments. The Ellesmerian foreland was buried by up to 4–5 km thick strata on top of the preserved sedimentary rocks. During the Triassic, the Sverdrup Basin strongly widened and extended at least ∼370 km further toward the east, as compared with previous reconstructions of the basin based on the preservation of Triassic deposits. Thermal history modeling suggests Late Cretaceous to early Cenozoic reheating, which may be caused by deposition associated with the Eurekan Orogeny and/or enhanced heat flow associated with continental breakup. Our data also show that low-temperature thermochronology is not suitable for resolving potential strike-slip movements along the Wegener Fault.