Compositional variations of Central Andean subduction-related igneous rocks reflect the plate-tectonic evolution of this active continental margin through time and space. In order to address the effect on magmatism of changing subduction geometry and crustal evolution of the upper continental plate during the Andean orogeny, we compiled more than 1500 major- and trace-element data points, and 650 Sr-, 610 Nd-, and 570 Pb-isotopic analyses of Mesozoic-Cenozoic (190–0 Ma) magmatic rocks in southern Peru and northern Chile (Central Andean orocline), mostly from new data and the literature. This data set documents compositional variations of magmas since Jurassic time, with a focus on the Neogene period, when major crustal thickening developed and its influence on magma composition was most pronounced. We relate the observed variations in Sr/Y, La/Yb, La/Sm, Sm/Yb, and Dy/Yb ratios, as well as in Sr-, Nd-, and Pb-isotopic ratios, to the crustal structure and evolution of the Central Andean orocline. In particular, the evolution of Dy/Yb and Sm/Yb ratios, which track the presence of the higher-pressure minerals amphibole and garnet, respectively, in the lower crust, documents that crustal thickness has grown through time. Spatial variations in trace elements and isotopic ratios further suggest that crustal domains of distinct composition and age have influenced magma composition through some assimilation. The crustal input in Quaternary magmas is quantified to have been between 7% and 18% by simple two-components mixing. When comparing our geochemical data set to the geological record of uplift and crustal thickening, we observe a correlation between the composition of magmatic rocks and the progression of Andean orogeny. In particular, our results support the interpretation that major crustal thickening and uplift were initiated in the mid-Oligocene (30 Ma) and that crustal thickness has kept increasing until present day. Our data do not support delamination as a general cause for major late Miocene uplift in the Central Andes and instead favor continued crustal thickening.