The regional tectono-stratigraphic evolution of the offshore SE Mediterranean passive margin is evaluated using detailed 2D seismic interpretations. New models for the development of the margin are proposed in the context of the break-up of northern Gondwana and the subsequent evolution of the southern Neotethys Ocean. The SE Mediterranean margin is segmented into distinct rift and transform-dominated tectonic domains as a consequence of multiple phases of rifting and continental break-up during the Middle Triassic–Middle Jurassic (c. 240–170 Ma) and the Late Jurassic–Mid-Cretaceous (c. 145–93 Ma), controlled by reactivation of pre-existing Pan-African basement fabrics and shear zones in varying regional stress fields. The pre-existing basement-involved extensional fault systems were repeatedly reactivated during major phases of inversion in the late Santonian–Maastrichtian (c. 84–65 Ma) and Middle–Late Eocene (c. 49–37 Ma) and episodes of mild inversion during the Oligocene–Early Pleistocene, as a consequence of the convergence of the African–Arabian and Eurasian plates and closure of the Neotethys oceans. The inversion history was fundamentally controlled by the structure and along-strike segmentation of the margin inherited from Neotethyan rifting.