Rhyolites of the Picabo volcanic field (10.4–6.6 Ma) in eastern Idaho are preserved as thick ignimbrites and lavas along the margins of the Snake River Plain (SRP), and within a deep (>3 km) borehole near the central axis of the Yellowstone hotspot track. In this study we present new O and Hf isotope data and U–Pb geochronology for individual zircons, O isotope data for major phenocrysts (quartz, plagioclase, and pyroxene), whole rock Sr and Nd isotope ratios, and whole rock geochemistry for a suite of Picabo rhyolites. We synthesize our new datasets with published Ar–Ar geochronology to establish the eruptive framework of the Picabo volcanic field, and interpret its petrogenetic history in the context of other well-studied caldera complexes in the SRP. Caldera complex evolution at Picabo began with eruption of the 10.44±0.27 Ma (U–Pb) Tuff of Arbon Valley (TAV), a chemically zoned and normal-δ¹⁸O (δ¹⁸O magma=7.9‰) unit with high, zoned ⁸⁷Sr/⁸⁶Sr_i (0.71488–0.72520), and low-ε_Nd(0) (−18) and ε_Hf(0) (−28). The TAV and an associated post caldera lava flow possess the lowest ε_Nd(0) (−23), indicating ∼40–60% derivation from the Archean upper crust. Normal-δ¹⁸O rhyolites were followed by a series of lower-δ¹⁸O eruptions with more typical (lower crustal) Sr–Nd–Hf isotope ratios and whole rock chemistry. The voluminous 8.25±0.26 Ma West Pocatello rhyolite has the lowest δ¹⁸O value (δ¹⁸O_melt=3.3‰), and we correlate it to a 1,000 m thick intracaldera tuff present in the INEL-1 borehole (with published zircon ages 8.04–8.35 Ma, and similarly low-δ¹⁸O zircon values). The significant (4–5‰) decrease in magmatic-δ¹⁸O values in Picabo rhyolites is accompanied by an increase in zircon δ¹⁸O heterogeneity from ∼1‰ variation in the TAV to >5‰ variation in the late-stage low-δ¹⁸O rhyolites, a trend similar to what is characteristic of Heise and Yellowstone, and which indicates remelting of variably hydrothermally altered tuffs followed by rapid batch assembly prior to eruption. However, due to the greater abundance of low-δ¹⁸O rhyolites at Picabo, the eruptive framework may reflect an intertwined history of caldera collapse and coeval Basin and Range rifting and hydrothermal alteration. We speculate that the source rocks with pre-existing low-δ¹⁸O alteration may be related to: (1) deeply buried and unexposed older deposits of Picabo-age or Twin Falls-age low-δ¹⁸O volcanics; and/or (2) regionally-abundant late Eocene Challis volcanics, which were hydrothermally altered near the surface prior to or during peak Picabo magmatism. Basin and Range extension, specifically the formation of metamorphic core complexes exposed in the region, could have facilitated the generation of low-δ¹⁸O magmas by exhuming heated rocks and creating the large water-rock ratios necessary for shallow hydrothermal alteration of tectonically (rift zones) and volcanically (calderas) buried volcanic rocks. These interpretations highlight the major processes by which supereruptive volumes of magma are generated in the SRP, mechanisms applicable to producing rhyolites worldwide that are facilitated by plume driven volcanism and extensional tectonics.