Supereruptive volumes of low-δ18O rhyolites define the Snake River Plain–Yellowstone Plateau volcanic province, begging the question of the sources and the processes by which 18O-depleted magmas are generated. New analyses show that Archean crustal xenoliths from the central and eastern Snake River Plain have normal-δ18O signatures of 6‰–9‰, precluding them as a low-δ18O source in the genesis of >10,000 km3 of low-δ18O (δ18O < 6‰) Snake River Plain rhyolites. Synthesis of O-Sr-Nd-Pb isotope data for Archean xenoliths and Snake River Plain magmas defines separate compositional fields of rhyolites and their crustal and mantle sources. Sr-O and Nd-O isotopic mixing models for the most recent volcanic fields in the eastern Snake River Plain, Yellowstone Plateau and Heise, show that normal-δ18O rhyolites have variable crust (∼30%–50%) and mantle (∼50%–70%) proportions that are specific for each eruption. Low-δ18O rhyolites can be traced along a genetic array of mixing lines from normal-δ18O rhyolite end members to a low-δ18O (∼–1‰) source. The data support a two-stage magma genesis process, in which normal-δ18O rhyolites are generated by partial melting and hybridization of the crust by mantle-derived basalt, and low-δ18O rhyolites tap ∼20%–80% of hydrothermally altered portions of normal-δ18O rhyolitic rocks. This two-stage magma genesis process may be applicable to other caldera systems around the world for which the characteristic O isotope depletions are either less pronounced or undiscovered.