In order to unravel the tectonic evolution of the north-central sector of the Sicily Channel (Central Mediterranean), a seismo-stratigraphic analysis of single- and multi-channel seismic reflection profiles has been carried out. This allowed to identify, between 20 and 50 km offshore the central-southern coast of Sicily, a ~80-km-long deformation belt, characterized by a set of WNW–ESE to NW–SE fault segments showing a poly-phasic activity. Within this belt, we observed: i) Miocene normal faults reactivated during Zanclean–Piacenzian time by dextral strike-slip motion, as a consequence of the Africa–Europe convergence; ii) releasing and restraining bend geometries forming well-developed pull-apart basins and compressive structures. In the central and western sectors of the belt, we identified local transpressional reactivations of Piacenzian time, attested by well-defined compressive features like push-up structures and fault-bend anticlines. The reconstruction of timing and style of tectonic deformation suggest a strike-slip reactivation of inherited normal faults and the local subsequent positive tectonic inversion, often documented along oblique thrust ramps. This pattern represents a key for an improved knowledge of the structural style of foreland fold-and-thrust belts propagating in a preexisting extensional domain. With regard to active tectonics and seismic hazards, recent GPS data and local seismicity events suggest that this deformation process could be still active and accomplished through deep-buried structures; moreover, several normal faults showing moderate displacements have been identified on top of the Madrepore Bank and Malta High, offsetting the Late Quaternary deposits. Finally, inside the northern part of the Gela Basin, multiple slope failures, originated during Pleistocene by the further advancing of the Gela Nappe, reveal tectonically induced potential instability processes.