We constrain the history of the Greenland Ice Sheet margin during the Holocene at Upernavik Isstrøm, a major ice stream in northwestern Greenland. Radiocarbon-dated sediment sequences from proglacial-threshold lakes adjacent to the present ice margin constrain deglaciation of the sites to older than 9.6 ± 0.1 ka. This age of deglaciation is confirmed with 10Be ages of 9.9 ± 0.1 ka from an island adjacent to the historical ice position. The lake sediment sequences also constrain the ice margin to have been less extensive than it is today for the remainder of the Holocene until ~ 1100 to ~ 700 yr ago, when it advanced into two lake catchments. The ice margin retreated back out of these lake catchments in the last decade. The early Holocene deglaciation in Melville Bugt, one of few locations around Greenland where a vast stretch of the current ice margin is marine-based, preceded deglaciation in most other parts of Greenland. Earlier deglaciation in this ice-sheet sector may have been caused by additional ablation mechanisms that apply to marine-based ice margins. Furthermore, despite ice-sheet models depicting this sector of Greenland as relatively stable throughout the Holocene, our data indicate a > 20 km advance-retreat cycle within the last millennium.