The western United States is one of Earth's most tectonically active regions, characterized by extensive crustal deformation through intraplate earthquakes and geodetic motion. Such intracontinental deformation is usually ascribed to plate boundary forces, lithospheric body forces, and/or viscous drag from mantle flow. However, their relative importance in driving crustal deformation remains controversial due to inconsistent assumptions on crustal and mantle structures in prior estimations. Here, we utilize a fully dynamic three-dimensional modeling framework with data assimilation to simultaneously compute lithospheric and convective mantle dynamics within the western United States. This approach allows for quantitative estimations of crustal deformation while accounting for the realistic three-dimensional lithospheric structure. Our results show the critical role of the complex lithospheric structure in governing intraplate deformation. Particularly, the interaction between the asthenospheric flow and lithospheric thickness step along the eastern boundary of the Basin and Range represents a key driving mechanism for localized crustal deformation and seismicity.