The Last Interglacial climatic optimum, ca. 128 ka, is the most recent climate interval significantly warmer than present, providing an analogue (albeit imperfect) for ongoing global warming and the effects of Greenland Ice Sheet (GIS) melting on climate over the coming millennium. While some climate models predict an Atlantic meridional overturning circulation (AMOC) strengthening in response to GIS melting, others simulate weakening, leading to cooling in Europe. Here, we present evidence from new proxy-based paleoclimate and ocean circulation reconstructions that show that the strongest warming in western Europe coincided with maximum GIS meltwater runoff and a weaker AMOC early in the Last Interglacial. By performing a series of climate model sensitivity experiments, including enhanced GIS melting, we were able to simulate this configuration of the Last Interglacial climate system and infer information on AMOC slowdown and related climate effects. These experiments suggest that GIS melt inhibited deep convection off the southern coast of Greenland, cooling local climate and reducing AMOC by ∼24% of its present strength. However, GIS melt did not perturb overturning in the Nordic Seas, leaving heat transport to, and thereby temperatures in, Europe unaffected.