Despite abundant Pleistocene calderas in the East African Rift and Afar, and the significance of regional tephra horizons for archaeological and paleoenvironmental dating, the entanglements of volcanoes and their eruptions with human behaviour and paleoecology have received little attention. Here, we focus on the intertwined human and eruptive history at Nabro, a caldera-topped volcanic massif close to the Red Sea littoral of Eritrea. Nabro exemplifies the antagonism of opportunities and threats posed by a large silicic volcano, active at least since the Middle Pleistocene and as recently as 2011. Using argon isotopic measurements, we establish the first chronology of key eruptive stages of Nabro and neighbouring Mallahle, revealing a history of explosive and effusive volcanism in the Middle and Late Pleistocene. Past eruptions were an important source of obsidian that was exchanged over long distances across land and sea during the Neolithic. We infer that the availability of high-quality obsidian, combined with Nabro’s favourable microclimate and proximity to the Red Sea coast, likely attracted humans to this volcanic landmark since the later Middle Pleistocene. Drawing on observations of the immediate consequences of the 2011 eruption on landscape and local pastoralist communities, we consider also the impacts of past volcanic cataclysms on human populations. In addition to the threat to life, explosive eruptions of Nabro circa 130 ka and 62 ka ago would have abruptly curtailed procurement of its obsidian resource. Our findings suggest further attention be paid to evaluating the significance of East African volcanic landscapes, eruptions and resources for understanding human behaviour in deep antiquity.