Abstract The GOCE (Gravity field and steady-state Ocean Circulation Explorer) mission, launched on March 2009, included a new type of satellite instrument, an on-board three-axis gradiometer able to measure the Earth's gravity gradients at the satellite height (255km). The potential of this new type of measurement and its derived products (i.e., global gravity field models), together with other land-based geophysical observables (Bouguer and geoid anomalies), to image sub-lithospheric thermal and compositional anomalies is evaluated in this study. We focus on the Atlantic-Mediterranean Transition Region (AMTR), the diffuse, transpressive contact between the Iberian Peninsula and North Africa. The present-day lithospheric structure in the area is characterized by a wide band of active deformation, large lateral variations in the lithosphere and the presence of a positive seismic-velocity anomaly in the uppermost mantle beneath the Betics and the westernmost Alboran Basin-Gibraltar Arc. Here, the perturbing effects of deep, sub-lithospheric density anomalies in GOCE gravity gradients and other land-based geophysical data are assessed, and its impact in lithospheric-scale geophysical-petrological modeling within a thermodynamically consistent framework analyzed. Some of the gravity gradients computed at the satellite altitude are rather sensitive to the presence of even a relatively small sub-lithospheric cold slab, like the one observed in the AMTR, showing the potential of the new GOCE data to map upper mantle anomalies. Lithospheric models ignoring the AMTR sub-lithospheric heterogeneities could be significantly biased. In particular, extreme changes of 4–6km and 60–70km in the crustal and lithospheric thickness, respectively, are required to include sub-lithospheric mantle contributions to land-based and satellite gravity data.