Past, present, and future ice sheet stability is closely linked to the dynamic behavior of major draining ice streams and surrounding ice shelves. While short observational records document the recent variability and acceleration of ice streams, the long-term dynamics of ice streams remain poorly documented. Here, we date the Pjetursson’s Moraine on Disko Island, Greenland, to 12.2 ± 0.6 ka and demonstrate that the Jakobshavn Isbræ (JI) ice stream collapsed during the middle of the Younger Dryas (YD) cold interval. We suggest that this collapse was due to the incursion of warm subsurface water under the ice shelf fronting the JI ice stream, as well as increased surface-air temperature and sea-surface temperature seasonality starting at the beginning of the YD cold interval. The triggered acceleration of the land-based JI and the delivery of icebergs into Disko Bugt potentially contributed to Heinrich Event 0 at the end of the YD. The collapse of the JI ice stream 12.2 ± 0.6 ka ago demonstrates that calving marine-based ice margins can respond rapidly to environmental changes. It provides a new benchmark for marine-terminating ice stream models.