Removal and thinning of cratonic lithosphere is believed to have occurred under different tectonic settings, for example, near subduction zones and above mantle plumes. Subduction-induced cratonic modification has been widely discussed; however, the mechanisms and dynamic processes of plume-induced lithospheric removal remain elusive and require further systematic investigation. In this study, we conduct a series of 2-D thermo-mechanical models to explore the dynamics of the removal and thinning of cratonic lithosphere due to the interaction between a mantle plume and a weak mid-lithosphere discontinuity (MLD) layer. Our modeling results suggest that the interaction between a mantle plume and weak MLD layer can lead to a large-scale removal of the cratonic lithosphere as long as the connection between the hot upwelling and weak MLD layer is satisfied. The presence of a vertical lithospheric weak zone and its closeness to the plume center play critical roles in creating a connection between the weak MLD and hot plume/asthenosphere. Furthermore, delamination of cratonic lithosphere is favored by a larger plume radius/volume, a higher plume temperature anomaly, and a lower viscosity of the MLD layer. A systematic comparison between subduction-induced and plume-induced lithospheric thinning patterns is further conducted. We summarize their significant differences on the origin and migration of melt generation, the water content in melts, and topographic evolution. The combination of numerical models and geological/geophysical observations indicates that mantle plume-MLD interaction may have played a crucial role in lithospheric removal beneath South Indian, South American and North Siberian Cratons.