The sedimentary record across the Canadian High Arctic, North Greenland and Svalbard is fragmentary, making regional correlation difficult. We seek new insights by integrating information from the preserved geological section with evidence of former stratigraphic units that are no longer present (missing section), using paleo-thermal methods to define episodes of deeper burial and subsequent exhumation. Parts of the region were affected by deformation induced by the Paleocene–Eocene movement of Greenland relative to the North American and Eurasian plates (the Eurekan Orogeny). However, our results indicate four discrete episodes of kilometre-scale exhumation before, during and after the Eurekan Orogeny that led to disruption of sedimentary basins across the region. (1) Regional Maastrichtian exhumation possibly reflects doming above the rising Iceland Plume. The plume impact at the base of the lithosphere contributed to the onset of mid-Paleocene sea-floor spreading west of Greenland that provided the driving force for the Eurekan Orogeny. (2) Localized Paleocene exhumation was caused by inversion of fault zones in the initial stage of the Eurekan Orogeny due to compression that also formed foreland basins and caused the West Spitsbergen Fold Belt. (3) Regional exhumation that began at the end of the Eocene postdates sea-floor spreading west of Greenland and thus represents post-Eurekan tectonics. This episode, which also affected regions far from the Eurekan Orogen, coincided with a major change in the North-East Atlantic spreading system. Transmission of stress from a shift in the motion of Africa relative to Europe may have contributed to these changes. (4) Regional, late Miocene uplift and erosion initiated the development of present-day landscapes. Our results show both local uplift events within the Eurekan Orogen and synchronous effects over large regions that require new ideas about the stresses driving horizontal and vertical movements of the earth’s crust.