Abstract Middle Eocene to early Oligocene intrusions, widespread in the Ruby Mountains–East Humboldt Range metamorphic core complex, Nevada, USA, provide insights into a major Paleogene magmatic episode and its relation to tectonism in the northeastern Great Basin. These intrusions, well-exposed in upper Lamoille Canyon, range in composition from gabbro to leucomonzogranite. They form small plutons, sheets, and dikes that intrude the metamorphic and granitic infrastructure of the core complex. Two types of Paleogene monzogranite were recognized. The first is exemplified by two of the larger intrusive bodies, the Snow Lake Peak and Castle Lake intrusions, which occur as sheet-like bodies near and at the structural base of metamorphosed Neoproterozoic and Cambrian Prospect Mountain Quartzite where it is inverted above Cambrian and Ordovician marble of Verdi Peak in the Lamoille Canyon nappe. Swarms of dikes are associated with these intrusions. U-Pb (zircon) ages range ca. 40–33 Ma and typically display relatively simple and minor inheritance. The rocks have the lowest εHf (zircon) and εNd (whole rock) of any of the middle Cenozoic granites. The second type of monzogranite, Overlook type, typically occurs as thin, isolated dikes and leucosome-like bodies in Late Cretaceous granites of the infrastructure, with no obvious relationship to the large monzogranite bodies. Overlook-type monzogranite displays complex zircon inheritance, yields igneous ages ca. 37–32 Ma, and has εHf (zircon) and εNd (whole rock) identical to those of Late Cretaceous granites in the core complex. These isotopic and field data indicate that Overlook-type monzogranite formed in situ through anatexis of host Cretaceous granites. A pervasive thermal event was required to stimulate this crustal melting. Gabbros from Lamoille Canyon and quartz diorite dated from 32 km away signal mantle-derived magmatism ca. 39–37 Ma (U-Pb, zircon) was a driver of crustal melting and hybridization. Eocene 40Ar/39Ar apparent ages on hornblende and biotite are consistent with syn- to post-magmatic extensional exhumation and decompression. Thus, the core complex provides a window into trans-crustal magmatism and insight into how such magmatism affected the Nevadaplano orogenic plateau. This Paleogene thermal pulse, which may relate to removal of the Farallon slab by delamination of mantle lithosphere, involved partial melting of the upper mantle and transfer of magma and heat to the Nevadaplano crust. Lower-crustal melting of Archean(?) to Paleoproterozoic rocks resulted in Snow Lake Peak–type magmas, and middle-crustal melting of granite in the infrastructure yielded Overlook-type magmas. This crustal magmatism, as exemplified by the intrusions in the core complex, likely played a role in destabilizing the Nevadaplano and its later collapse during middle Miocene extension. The Paleogene intrusions and associated structural features also provide insight into the evolution of the core complex through either the buoyant upwelling of a melt-rich diapir (gneiss-dome model) or buoyant upwelling of the melt-rich middle crust synchronous with a west-rooted mylonitic shear zone (extensional shear-zone model). We favor a hybrid that incorporates both models.