The paleoenvironmental and paleogeographic development of the Norwegian–Greenland seaway remains poorly understood, despite its importance for the oceanographic and climatic conditions of the Paleocene–Eocene greenhouse world. Here we present analyses of the sedimentological and paleontological characteristics of Paleocene–Eocene deposits (between 63 and 47 million years old) in northeast Greenland, and investigate key unconformities and volcanic facies observed through seismic reflection imaging in offshore basins. We identify Paleocene–Eocene uplift that culminated in widespread regression, volcanism, and subaerial exposure during the Ypresian. We reconstruct the paleogeography of the northeast Atlantic–Arctic region and propose that this uplift led to fragmentation of the Norwegian–Greenland seaway during this period. We suggest that the seaway became severely restricted between about 56 and 53 million years ago, effectively isolating the Arctic from the Atlantic ocean during the Paleocene–Eocene thermal maximum and the early Eocene.