Mocho-Choshuenco volcano (39.9°S, 72.0°W) produced ∼75 explosive eruptions following retreat of the >1.5-km-thick Patagonian Ice Sheet associated with the local Last Glacial Maximum (LGM, from 35 to 18 ka). Here, we extend this record of volcanic evolution to include pre- and syn-LGM lavas that erupted during the Pleistocene. We establish a long-term chronology of magmatic and volcanic evolution and evaluate the relationship between volcanism and loading/unloading of the Patagonian Ice Sheet via twenty-four 40Ar/39Ar and two 3He age determinations integrated with stratigraphy and whole-rock compositions of lava flows and glass compositions of tephra. Our findings reveal that the edifice is much younger than previously thought and preserves 106 km3 of eruptive products, of which 50% were emplaced immediately following the end of the penultimate glaciation and 20% after the end of the LGM. A period of volcanic inactivity between 37 and 26 ka, when glaciers expanded, was followed by the eruption of incompatible element-rich basaltic andesites. Several of these syn-LGM lavas dated between 26 and 16 ka, which crop out at 1500−1700 m above sea level, show ice contact features that are consistent with emplacement against a 1400- to 1600-m-thick Patagonian Ice Sheet. Small volume dacitic eruptions and two explosive rhyolitic eruptions dominate the volcanic output from 18 to 8 ka, when the Patagonian Ice Sheet began to retreat rapidly. We hypothesize that increased lithostatic loading as the Patagonian Ice Sheet grew prohibited dike propagation, thus stalling the ascent of magma, promoting growth of at least three discrete magma reservoirs, and enhancing minor crustal assimilation to generate incompatible element-rich basaltic andesitic to dacitic magmas that erupted between 26 and 17 ka. From an adjacent reservoir, incompatible element-poor dacites erupted from 17 to 12 ka. These lava flows were followed by the caldera-forming eruption at 11.5 ka of 5.3 km3 of rhyolite from a deeper reservoir atop which a silicic melt lens had formed and expanded. Subsequent eruptions of oxidized dacitic magmas from the Choshuenco cone from 11.5 to 8 ka were followed by andesitic to dacitic eruptions at the more southerly Mocho cone, as well as small flank vent eruptions of basaltic andesite at 2.5 and 0.5 ka. This complex history reflects a multi-reservoir plumbing system beneath Mocho-Choshuenco, which is characterized by depths of magma storage, oxidation states, and trace element compositions that vary over short periods of time (<2 k.y.).