Sermeq Kujalleq, Greenland's largest glacier, has significantly retreated since the late 1990s in response to warming ocean temperatures. Using a large-ensemble approach, our simulations show that the retreat is mainly initiated by the arrival of warm water but sustained and accelerated by the glacier's position over deeper bed troughs and vigorous calving. We highlight the need for models of ice mélange to project glacier behavior under rapid calving regimes.