A widespread unconformity between Ordovician metasedimentary rocks and nonmetamorphosed Mesozoic sedimentary rocks across the Eastern Cordillera of Bolivia provides evidence for significant pre-Late Cretaceous deformation and erosion. In this paper, we refine the middle to late Paleozoic tectonic history of the central Andean segment of Gondwana's western margin. We combine Raman spectroscopy of carbonaceous material (RSCM) thermometry with semi-quantitative deformation temperature estimates from quartz recrystallization microstructures and published illite crystallinity values from Cambrian-Devonian sedimentary rocks that span the Eastern Cordillera of southern Bolivia at ~21°S. Estimates of peak temperature and deformation temperature range primarily between ~220 and ~ 400 °C and show a general increase with depth that defines a metamorphic field gradient between ~37 and ~ 47 °C/km. Temperatures obtained from Ordovician rocks directly below the unconformity require erosion of a > ~5 km overburden prior to the Late Cretaceous, which was likely accomplished by a combination of distributed cleavage development and Paleozoic folding and thrust faulting revealed from cross-section reconstructions. The peak temperature data are incorporated into thermal models along with published illite KAr, zircon (UTh)/He, and zircon fission-track cooling ages that refine the timing of Paleozoic orogenesis in the central Andes. We interpret shortening-related flexural subsidence driven by cratonward growth of a pre-Andean orogenic wedge along the western margin of Gondwana, with peak temperature conditions attained during eastward advance of a foreland basin between ~420 and ~ 318 Ma during the Devonian-Carboniferous Gondwanide Orogeny. Erosional exhumation between ~352 and ~ 294 Ma was the result of continued growth and eastward expansion of the associated Transpampean tectonic highland across the Eastern Cordillera. The growth of this pre-Andean contractional orogen coincided with global plate reorganization and the reestablishment of subduction and arc magmatism along the western margin of Gondwana, as indicated by a significant influx of Carboniferous arc-related detritus into the foreland basin system.