Holocene paleohydrology reconstruction is derived combining planktonic and benthic stable oxygen and carbon isotopes, sea surface temperatures (SSTs) and oxygen isotope composition of seawater (δ18Ow) from a high sedimentation core collected in the South Adriatic Sea (SAS). Core chronology is based on 10 AMS 14C measures on planktonic foraminifera and tephra layers. Results reveal two contrasted paleohydrological periods that reflect (i) a marked lowering of δ18Ow/salinity during the early to mid-Holocene (11.5 ka to 6.3 ka), including the two-step sapropel S1 deposition, followed during the mid- to upper Holocene by (ii) a prevailing period of increased salinity and enhanced arid conditions in the South Adriatic Basin. Superimposed on these trends, short-term centennial-scale hydrological events punctuated the Holocene period in the SAS. During the early to mid-Holocene, two main SST coolings together with prominent δ18Ow/salinity lowering delineate the sapropel S1 interruption and the post-sapropel phase between 7.3 to 6.3 ka. After 6 ka, centennial-scale δ18Ow and G. bulloides δ13C lowering, mostly centered between 3 to 0.6 ka, reflect short-term hydrological changes related to more intensive runoff of the Po and/or Apennine rivers. These short-term events, even of lesser amplitude compared to the early to mid-Holocene period, may have induced a lowering of sea surface density and consequently reduced and/or inhibited the formation of deep bottom waters in the SAS. Comparison of the emerging centennial- to millennial-scale hydrological record with previous climatic records from the central Mediterranean area and north of the Alps reveal possible synchronicities (within the radiocarbon-dating uncertainty) between phases of lower salinity in the SAS and periods of wetter climatic conditions around the north-central Adriatic Sea. Finally, wavelet analyses provide new clues about the potential origin of climate variability in the SAS, confirming the evidence for a mid-Holocene transition in the central Mediterranean climate and the dominance of a ~1670-yr periodicity after 6 ka, reflecting a plausible connection with the North Atlantic climate system.