South America lost around 52 genera of mammals during a worldwide event known as the Late Quaternary Extinction episode. More than 80% of South American mammals weighing > 44 kg succumbed. Analysis of the megafaunal extinction chronology in relation to human arrival and major climate changes have revealed slightly different extinction patterns in different eco‐regions of the continent, highlighting the importance of detailed regional analysis in order to understand how the possible drivers of extinction operated. Here we present an analysis of the megafaunal extinction in the Última Esperanza (UE) area of southwestern Patagonia, Chile. We have compiled a comprehensive chronology of megafaunal extinctions and earliest human occupation between 18–7 cal ka BP, based on radiocarbon dates from published literature. We calculated confidence intervals using the GRIWM method to estimate the times of human arrival and megafaunal local extinctions, and then compared these events to the timing of major climate and vegetation changes, fire frequency increase, and the Reclús volcanic eruption. Our results suggest that a combination of human impacts and climate–vegetation change drove megafaunal extinctions in the UE area, with the balance of factors being taxon specific; the volcanic eruption does not seem to have exacerbated extinctions. Competition between humans and mega‐carnivores seems to be the most plausible cause for the extinction of the mega‐carnivores. Coexistence of humans with extinct horses, extinct camels, and mylodonts for several thousand years rules out a scenario of blitzkrieg overkill of megafauna by humans. The transition of vegetation from cold grasslands to Nothofagus forests corresponds with the disappearance of Hippidion saldiasi and Lama cf. owenii. The later full establishment of Nothofagus forests and an increasing fire frequency coincided with the disappearance of mylodonts. A climate‐driven reduction of open environments plausibly reduced herbivore's populations making them susceptible to local extinction.
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