The control of upper mantle-lithosphere interactions (MLI) on compressional tectonics is not well resolved. This applies to the role of MLI in triggering of subduction initiation or lithosphere mantle (LM) downwellings. We present results of thermo-mechanically thermo-dynamically coupled numerical experiments that are consistent with an array of recent geophysical constraints on lithosphere and upper mantle rheology and structure. We demonstrate that MLI can lead to initiation of continental lithosphere subduction, inducing its spontaneous downthrusting to depths of 300–500 km upon plume impingement of the lithosphere. This downthrusting is pre-conditioned by rheological stratification of visco-elasto-plastic lithosphere and its free surface. The subsequent evolution of the slab is governed by phase changes and its interactions with the surrounding mantle. We demonstrate that the mode of MLI is strongly affected by the lateral heterogeneities and the presence of suture zones in the lithosphere.