The Alaska Peninsula is a landscape defined by volcanic, tectonic, and glacial processes, and life throughout is conditioned on the interactions among them. During the middle Holocene (ca. 4100–3600 yr ago), intense caldera-forming eruptions of the Aniakchak and Veniaminof volcanoes changed the shape of the central portion of the Peninsula dramatically, and had significant and perhaps devastating impacts on both terrestrial and marine biota. Here we evaluate the severity of these impacts by tracking human settlement patterns using 75 unique radiocarbon (14C) age determinations on buried cultural features from the central Alaska Peninsula. Coastal regions were re-colonized within a few hundred years while river systems most proximate to the volcanoes were uninhabited for up to 1500 years following the most severe eruptions. Patterns of human settlement may also document previously unrecorded landscape change throughout the region, and further contribute to our understanding of post-volcanic ecological succession.