Late Cenozoic opening of the Fram Strait led to formation of the NW–SE striking, eastern North Greenland oblique-shear margin at transition from the Norwegian–Greenland Sea to the SW Eurasia Basin. Onshore geology exposed on large peninsulas in front of the major Greenland Inland Ice reveals a highly complex, Paleozoic–early Cenozoic pre-opening setting. However, due to extreme ice conditions, very little is known about the offshore areas seawards of – and between – the peninsulas. Consequently, prevailing structural-tectonic models of the margin tend to be significantly oversimplified and inadequate. We present the first, combined onshore–offshore, model of the margin integrating onshore outcrops with potential field data, new offshore seismic reflection data and receiver-function analysis of seismic broad band data. The results reveal a margin which is far more complex than previously anticipated. In particular, we interpret strong margin segmentation along N/NE-striking fault structures. The structures are likely to have formed by Late Mesozoic–early Cenozoic strike-slip tectonics and have continued to be active during the late Cenozoic. A more than 8 km deep sedimentary basin is interpreted to underlie the central Wandel Sea, confined by these N/NE-striking structures. We suggest that similar margin segmentation affected the conjugate Yermak Plateau–North Svalbard margin as well as parts of the NE Greenland margin to the SE. Hence, the results have important implications for the general understanding of the Mesozoic–early Cenozoic development of the intra-continental De Geer Mega-shear Region between North Greenland and Eurasia.