Despite a large number of studies, the long-term and millennial to centennial-scale climatic variability in the Mediterranean region during the last deglaciation and the Holocene is still debated, including in the southern Central Mediterranean. In this paper, we present a new marine pollen sequence (core MD04-2797CQ) from the Siculo-Tunisian Strait documenting the regional vegetation and climatic changes in the southern Central Mediterranean during the last deglaciation and the Holocene. The MD04-2797CQ marine pollen sequence shows that semi-desert plants dominated the vegetal cover in the southern Central Mediterranean between 18.2 and 12.3 ka cal BP, indicating prevailing dry conditions during the deglaciation, even during the Greenland Interstadial (GI)-1. Across the transition Greenland Stadial (GS)-1 – Holocene, Asteraceae-Poaceae steppe became dominant till 10.1 ka cal BP. This record underlines with no chronological ambiguity that even though temperatures increased, deficiency in moisture availability persisted into the early Holocene. Temperate trees and shrubs with heath underbrush or maquis expanded between 10.1 and 6.6 ka, corresponding to Sapropel 1 (S1) interval, while Mediterranean plants only developed from 6.6 ka onwards. These changes in vegetal cover show that the regional climate in southern Central Mediterranean was wetter during S1 and became drier during the mid- to late Holocene. Wetter conditions during S1 were likely due to increased winter precipitation while summers remained dry. We suggest, in agreement with published modeling experiments, that the early Holocene increased melting of the Laurentide Ice Sheet in conjunction with weak winter insolation played a major role in the development of winter precipitation maxima in the Mediterranean region in controlling the strength and position of the North Atlantic storm track. Finally, our data provide evidence for centennial-scale vegetation and climatic changes in the southern Central Mediterranean. During the wet early Holocene, alkenone-derived cooling episodes are synchronous with herbaceous composition changes that indicate muted changes in precipitation. In contrast, enhanced aridity episodes, as detected by strong reduction in trees and shrubs, are recorded during the mid- to late Holocene. We show that the impact of the Holocene cooling events on the Mediterranean hydroclimate depend on baseline climate states, i.e. insolation and ice sheet extent, shaping the response of the mid-latitude atmospheric circulation.