A multiproxy study combining calcareous plankton assemblages (coccolithophore and planktonic foraminifera), terrestrial (n-alkanes) and marine (alkenones) biomarkers was carried out in a sediment core (ND14Q-AR2) from the South Adriatic Sea. The focus of the study is to investigate millennial-to-centennial scale climate variability in the Eastern Mediterranean during the last deglaciation, between 20 and 11 ka BP. The high-resolution reconstruction allows for the characterization of the impact of the Heinrich Stadial 1 (HS1, here identified between 17.1 and 14.9 ka BP) at a centennial/multi-decadal time scale resolution. Based on terrestrial proxies, the HS1 interval has a two-fold partition: HS1a (17.1–15.9 ka BP), characterized by decreasing temperatures and relative high humidity, and HS1b (15.9–14.9 ka BP), characterized by the coldest temperatures and drier conditions on land. Terrestrial proxies suggest changes in moisture availability on land and ice melting delivery from the Alps during HS1. This period is followed by the Bølling-Allerød record (B-A, 14.9–12.3 ka BP) indicating ameliorated climate conditions and distinct local hydrological signals, related to global melt events similar to the Melt Water Pulse-1A. Finally, the comparison of our results with other Northern Hemisphere climatic records shows a good correspondence between the temperature variations in the South Adriatic Sea and the Greenland ice core oxygen isotope record, highlighting the climatic response of the South Adriatic to global climate variations. Comparison with other Mediterranean paleoclimatic records suggests a two-steps reorganization of the ocean/atmospheric circulation during the HS1 in the mid- and low-latitudes during the HS1 interval, but also a connection with the tropical Northern Hemisphere climate.