High-grade (amphibolite–granulite facies) tectono-metamorphic domains in the Sefwi terrane of Ghana are separated from adjacent lower-grade (greenschist facies) greenstone belts by two main shear zones. The high-grade rocks presumably exhumed along the sinistral shear zones during the D2 ENE-WSW transtension (~2073 Ma). To better understand the role boundary conditions and the spatial relationship of faults play in the exhumation of partially molten lower crust in the Sefwi terrane, ten 3D thermomechanical models have been constructed. The results show that the normal component of velocity boundary conditions mainly controls the exhumation (8–10 km) of the lower crust along pre-existing faults, while the exhumation in the relay zones between faults is controlled by the obliquity between the applied extensional velocity vector and the vertical wall on which it is applied. The strike of the exhumation belt made of partially molten lower crust rocks in the relay zone is sub-orthogonal to the horizontal maximum stretching axis. The isostatic compensation from low-density upper mantle to overlying crust (thinning) is higher under transtension than under extension. The lower crust exhumation influenced by inherited shear zones (ductile) can be used to better understand the loci of the high-grade rocks in the Sefwi terrane. We suggest that the Kukuom-Juaboso domain composed of amphibolite–migmatite facies rocks probably resulted from the concentration of partially molten rocks in the relay zone between the Ketesso and Kenyase shear zones during the D2 ENE-WSW transtension. The two shear zones probably underwent two main stages for growth and maturation from the D1 to D2 phases. The regional exhumation of the high-grade rocks in the Sefwi terrane probably occurred within < 5 Ma.