We investigate the putative Pliocene–Quaternary removal of mantle lithosphere from beneath the southern Sierra Nevada region using a synthesis of subsidence data from the Great Valley, and geomorphic relations across the Sierra Nevada. These findings are used to test the results and predictions of thermomechanical modeling of the lithosphere removal process that is specific to the Sierra Nevada, as presented in an accompanying paper referenced here as Part I. Our most successful thermomechanical model and the observational data that it explains are further bundled into an integrated physiographic evolution–geodynamic model for the three-dimensional epeirogenic deformation field that has affected mainly the southern Sierra Nevada–San Joaquin Basin region as a result of underlying mantle lithosphere removal. The coupled Sierra Nevada mountain range and Great Valley basin are recognized as a relatively rigid block (Sierra Nevada microplate) moving within the San Andreas–Walker Lane dextral plate juncture system. Our analysis recognizes that the Sierra Nevada possessed kilometer-scale local and regional paleotopographic relief, and that the Great Valley forearc basin possessed comparable structural relief on its principal stratigraphic horizons, both dating back to the end of Cretaceous time. Such ancient paleorelief must be accounted for in considering late Cenozoic components of uplift and subsidence across the microplate. We further recognize that Cenozoic rock and surface uplift must be considered from the perspectives of both local epeirogeny driven by mantle lithosphere removal, and regional far-field–forced epeirogeny driven by plate tectonics and regional upper-mantle buoyancy structure. Stratigraphic relations of Upper Cretaceous and lower Cenozoic marine strata lying on northern and southern Sierra Nevada basement provide evidence for near kilometer-scale rock uplift in the Cenozoic. Such uplift is likely to have possessed positive, and then superposed negative (subsidence) stages of relief generation, rendering net regional rock and surface uplift. Accounting for ancient paleorelief and far-field–driven regional uplift leaves a residual pattern whereby ∼1200 m of southeastern Sierra crest rock and similar surface uplift, and ∼700 m of spatially and temporally linked tectonic subsidence in the southern Great Valley were required in the late Cenozoic by mantle lithosphere removal. These values are close to the predictions of our modeling, but application of the model results to the observed geology is complicated by spatial and temporal variations in the regional tectonics that probably instigated mantle lithosphere removal, as well as spatial and temporal variations in the observed uplift and subsidence patterns. Considerable focus is given to these spatial-temporal variation patterns, which are interpreted to reflect a complex three-dimensional pattern resulting from the progressive removal of mantle lithosphere from beneath the region, as well as its epeirogenic expressions. The most significant factor is strong evidence that mantle lithosphere removal was first driven by an east-to-west pattern of delamination in late Miocene–Pliocene time, and then rapidly transitioned to a south-to-north pattern of delamination in the Quaternary.