Successive caldera-forming eruptions from ca. 30 to 25 Ma generated a large nested caldera complex in western Nevada that was subsequently dissected by Basin and Range extension, providing extraordinary cross-sectional views through diverse volcanic and plutonic rocks. A high-resolution oxygen isotopic study was conducted on units that represent all major parts of the Job Canyon, Louderback Mountains, Poco Canyon, and Elevenmile Canyon caldera cycles (29.2−25.1 Ma), and several Cretaceous plutons that flank the Stillwater caldera complex. We provide new oxygen and strontium isotope data for 12 additional caldera centers in the Great Basin, which are synthesized with >150 published oxygen and strontium isotope analyses for regional Mesozoic basement rocks. Stillwater zircons span a large isotopic range (δ¹⁸O_zircon of 3.6‰−8.2‰), and all caldera cycles possess low-δ¹⁸O zircons. In some cases, they are a small proportion of the total populations, and in others, they dominate, such as in the low-δ¹⁸O rhyolitic tuffs of Job Canyon and Poco Canyon (δ¹⁸O_zircon = 4.0‰−4.3‰; δ¹⁸O_magma = 5.5‰−6‰). These are the first low-δ¹⁸O rhyolites documented in middle Cenozoic calderas of the Great Basin, adding to the global occurrence of these important magma types that fingerprint recycling of shallow crust altered by low-δ¹⁸O meteoric waters. The appearance of low-δ¹⁸O rhyolites in the Stillwater caldera complex is overprinted on a Great Basin−wide trend of miogeoclinal sediment contribution to silicic magmas that elevates δ¹⁸O compositions, making identification of ¹⁸O depletions difficult. Though not a nominally low-δ¹⁸O rhyolite, the tuff of Elevenmile Canyon possesses both low-δ¹⁸O and high-δ¹⁸O zircon cores that are overgrown by homogenized zircon rims that approximate the bulk zircon average, pointing to batch assembly of isotopically diverse upper crustal melts to generate one of the most voluminous (2500−5000 km³) tuff eruptions in the Great Basin. Despite overlapping in space and time, each caldera-forming cycle of the Stillwater complex has a unique oxygen isotope record as retained in single zircons. Most plutons that were spatially and temporally coincident with calderas have isotopic compositions that diverge from the caldera-forming tuffs and cannot be their cogenetic remnants.