Circulation of water masses, sediment, and biotope between the sub-basins of the Mediterranean Sea strongly depends on morphological oceanic gateways. These geological features react to geodynamic reorganisation through volcanism, vertical movements, and/or the segmentation of sedimentary basins. Despite the palaeogeographic relevance of straits and oceanic-gateways, their evolution and impact on sedimentary transports and deposition in the Mediterranean remain in general poorly constrained. The Gargano-Pelagosa gateway is here first recognized as an influential element of the palaeogeographic/environmental evolution of the central-southern Apenninic foredeep and wedge-top domains during the Messinian, as shown by the integration of (i) seismic lines, (ii) well information from the Adriatic Sea, and (iii) a review of both onshore and offshore structural data and Messinian depositional environments. A palinspastic evolution is proposed for the Apennine and south Adriatic foredeeps during the Messinian Salinity Crisis (MSC: 5.97–5.33 Ma). We highlight the implication of the pre-MSC structural legacy and the development of the Apennine and Dinarid-Albanian chains in 1) the isolation of the Apennine foredeep from the deep central Mediterranean domains at the peak of the MSC; 2) the vertical movements at the Gargano-Pelagosa structure and the Apulian Platform and 3) their implication in the deposition of a chaotic sedimentary body.