The lithospheric structure of Antarctica is still under‐explored. Moho depth estimate studies are in disagreement by more than 10 km in several regions, including for example the hinterland of the Transantarctic Mountains. Taking account the sparseness of seismological stations and the non‐uniqueness of potential field methods, inversions of Moho depth are performed here based on satellite gravity data in combination with currently available seismically constrained Moho depth estimates. Our results confirm that a lower density contrast at the Moho is present under East Antarctica than beneath West Antarctica. A comparison between the Moho depth derived from our inversion and an Airy‐isostatic Moho model also reveals a spatially variable buoyancy contribution from the lithospheric mantle beneath contrasting sectors of East Antarctica. Finally, to test the plausibility of different Moho depths scenarios for the Transantarctic Mountains–Wilkes Subglacial Basin system, we present 2‐D lithospheric models along the TAMSEIS/GAMSEIS seismic profile. Our models show that if a moderately depleted lithospheric mantle of inferred Proterozoic age underlies the region, then a shallower Moho is more likely beneath the Wilkes Subglacial Basin. If however, re‐fertilisation processes occurred in the upper mantle, for example in response to Ross‐age subduction, then a deeper Moho scenario is preferred. We conclude that 3D lithospheric modeling, coupled with the availability of new seismic information in the hinterland of the Transantarctic Mountains is required to help resolve this controversy, thereby also reducing the ambiguities in geothermal heat flux estimation beneath this key part of the East Antarctic Ice Sheet.