The Turkana Depression separates the uplifted Ethiopian and East African Plateaus. It was the site, in Mesozoic times, of a failed episode of NE–SW-oriented rifting (the Anza Rift), but now hosts E–W-oriented Nubia–Somalia separation at the junction between the Main Ethiopian Rift in the north and the Eastern Rift to the south. However, the time-integrated effect of these rifting phases on crustal and lithospheric mantle architecture and thermal structure is poorly understood. Utilising data from new seismograph networks in the Turkana Depression and northern Tanzania Craton, we produce a detailed anisotropic crustal and uppermost mantle shear-wave velocity model of the region. Within the Tanzania Craton, slightly lower uppermost mantle wavespeeds (4.4–4.5 km/s) compared to neighbouring regions, and coincident rift-parallel crustal anisotropy, imply the Nyanza Rift developed in relatively weak mobile belt lithosphere between two refractory Archean blocks. At upper-crustal (≲10 km) depths in the Turkana Depression, the slowest velocities (≲3.2 km/s) are attributed to thick Mesozoic-age sedimentary basins. Nowhere within the Depression is the mid-to-lower crust or lithospheric mantle associated with wavespeeds as slow, or seismic anisotropy as strong, as that observed below the melt-rich central and northern Main Ethiopian Rift (MER) and Ethiopian Plateau further north. High upper mantle wavespeeds (≳4.5 km/s), coinciding with the broadening of MER-rifting into southern Ethiopia, confirm the presence of refractory Proterozoic lithosphere acting as a rheological boundary to rift development. Thinned crustal zones associated with failed Mesozoic Anza rifting are also underlain by fast wavespeed (>4.5 km/s) mantle lithosphere, implying this area has resisted significant thermomechanical modification from Miocene-Recent extension and magmatism. Pre-existing crustal thin zones do not, therefore, necessarily represent zones of plate-weakness where subsequent phases of rifting will develop.