The transition zone between western and central Mediterranean domains presents a key area to investigate kinematic interactions within the adjacent orogen systems such as the easternmost Atlas foreland‐and‐thrust belt. Gravity and seismic data revealed a highly structured basement, characterizing a series of structural highs and lows delimited by high‐angle N‐S, E‐W, and NW‐SE extensional faults. This basement architecture is inherited from successive extensional events related to the openings of the Triassic‐Early Cretaceous Tethys oceans (i.e., Alpine Tethys, Ligurian Tethys, and Mesogea). Throughout this period, this mosaic of continental blocks significantly controlled the thickness and facies distributions. Early stages of diapirism took place along these basement faults and allowed maximum subsidence in minibasins revealed by the development of growth strata. In response to the Late Cretaceous‐Eocene shortenings, these extensional faults have been reactivated as trasnpressional shear zones, giving rise to narrow pop‐up structures. In addition, gravity modeling indicates crustal thinning and deep‐rooted faults affecting the crust south of the Zaghouan Thrust and along E‐W transfer zones. From the late Miocene, a drastic change in the stress regime is attributed to the effect of the adjacent Sicily channel on the study area. This promotes crustal thinning, basin subsidence, and channeling up of mantle‐derived helium along lithospheric‐scale weak zones. Our results give rise to new insights into the reactivation of inherited weakness zones of southern Tethys margin in response to the complex interaction between African and Eurasian plates accommodated by subduction, rollback, collision, and slab segmentation.