South Sister volcano, Oregon Cascade Range, USA, has repeatedly erupted rhyolite since ca. 40 ka. The youngest such eruptions are the ca. 2 ka Rock Mesa and Devils Chain rhyolites, erupted several hundred years apart from two multi-vent complexes separated by 3–6 km. Fe-Mg interdiffusion models of orthopyroxene rims from both rhyolites produce timescales up to several-thousand years, but dominantly decades-to-centuries. Notably, the timescales of step-normal zoned orthopyroxene rims (i.e., normally zoned with a steep chemical gradient) from the Rock Mesa rhyolite are longer than those of reversely zoned crystals, whereas the Devils Chain produced mostly decadal timescales for both zoning types. Despite the proximity and broadly similar products of these episodes, their respective timescales indicate distinct sequences of events leading up to each eruption. The Rock Mesa timescales record centuries of magma chamber growth followed by decades of predominantly magma rejuvenation, reorganization, and destabilization. In contrast, the Devils Chain episode was preceded by a single episode of coupled rhyolite extraction, rejuvenation, and hybridization. Rare, high-An plagioclase cores and evidence of reheating implicate cryptic emplacement of mafic magma at the base of the rhyolite reservoirs. However, the diffusion timescales do not unequivocally support a single magma recharge event that affected both. Fluid fluxing and the reorganization of melt into buoyant magma chambers likely provided the source of increasing pressurization that initiated each eruption after several decades. Geodetic models of ongoing deformation west of South Sister could consider these processes in addition to magma emplacement.