A voluminous (>600 km3) and long-lived (~520–75 ka) phase of rhyolitic eruptions followed collapse of the Yellowstone caldera 640 ka. Whether these eruptions represent a dying cycle, or the growth of a new magma chamber, remains an important question. We use new U–Th zircon ages and δ18O values determined by ion microprobe, and sanidine Pb isotope ratios determined by laser ablation, to investigate the genesis of voluminous post-caldera rhyolites. The oldest post-caldera rhyolites, erupted between ~520 and 470 ka, exhibit extreme age and oxygen isotopic heterogeneity, requiring derivation from individual parcels of low-δ18O melts. We find a progressive increase in zircon homogeneity for rhyolite eruptions from ~260 to 75 ka, with homogeneous low-δ18O zircon values of 2.7–2.8‰ that are in equilibrium with low-δ18O host melts for the majority of the youngest eruptions. New sanidine Pb isotope data define separate arrays for post-caldera rhyolites and the caldera-forming tuffs that preceded them, indicating that they were not sourced from a mushy Lava Creek Tuff batholith that remained after caldera collapse. Rather, our new age and isotopic data indicate that the post-caldera rhyolites were generated by remelting of a variety of intracaldera source rocks, consisting of pre-Lava Creek Tuff volcanic and plutonic rocks and earlier erupted post-Lava Creek Tuff rhyolites. Batch assembly of low-δ18O melts starting at ~260 ka resulted in progressive homogenization, followed by differentiation and cooling up until the last rhyolite eruption ~75 ka, a trend that we interpret to be characteristic of a dying magma reservoir beneath the Yellowstone caldera.