We document the mineralogical and geochemical composition of tephra layers identified in the late Quaternary sediments of Puyehue Lake (Southern Volcanic Zone of the Andes, Chile, 40°S) to identify the source volcanoes and to present the first tephrostratigraphic model for the region. For the last millennium, we propose a multi-criteria correlation model based on five tephra layers identified at seven coring sites. The two upper tephras are thin fine-grained green layers composed of more than 80% rhyodacitic glass shards, and associated to the AD 1960 and AD 1921–22 eruptions of the Puyehue-Cordon de Caulle volcanic complex. The third tephra is a sandy layer dominated by orthopyroxene, and related to the AD 1907 eruption of Rininahue maar. An olivine-rich tephra was deposited at the end of the 16th century, and a tephra characterized by a two-pyroxene association marks the second half of the first millennium AD. In addition, we detail the tephra succession of an 11.22-m-long sediment core covering the last 18,000 yr. The results demonstrate that the central province of the Southern Volcanic Zone has been active throughout the last deglaciation and the Holocene, with no increase in volcanic activity during glacial unloading.