We report oxygen isotope compositions of phenocrysts and U-Pb ages of zircons in four large caldera-forming ignimbrites and post-caldera lavas of the Heise volcanic field, a nested caldera complex in the Snake River Plain, that preceded volcanism in Yellowstone. Early eruption of three normal δ18O voluminous ignimbrites with δ18Oquartz = 6.4‰ and δ18Ozircon = 4.8‰ started at Heise at 6.6 Ma, and was followed by a 2‰–3‰ δ18O depletion in the subsequent 4.45 Ma Kilgore caldera cycle that includes the 1800 km3 Kilgore ignimbrite, and post-Kilgore intracaldera lavas with δ18Oquartz = 4.3‰ and δ18Ozircon = 1.5‰. The Kilgore ignimbrite represents the largest known low-δ18O magma in the Snake River Plain and worldwide. The post-Kilgore low δ18O volcanism likely represents the waning stages of silicic magmatism at Heise, prior to the reinitiation of normal δ18O silicic volcanism 100 km to the northeast at Yellowstone. The occurrence of low δ18O magmas at Heise and Yellowstone hallmarks a mature stage of individual volcanic cycles in each caldera complex. Sudden shifts in δ18O of silicic magmas erupted from the same nested caldera complexes argue against any inheritance of the low δ18O signature from mantle or crustal sources. Instead, δ18O age trends indicate progressive remelting of low δ18O hydrothermally altered intracaldera rocks of previous eruptions. This trend may be generally applicable to older caldera complexes in the Snake River Plain that are poorly exposed.