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 ε_Hf (zircon) and ε_Nd (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 ε_Hf (zircon) and ε_Nd (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.