Anthropogenic climate change is occurring at an unprecedented rate, and the magnitude of that change is expected to rival levels that characterize Earth’s largest extinction events. Despite the importance for future projections, understanding of the underlying mechanisms by which climate mediates extinction remains limited. The fossil record provides the unique opportunity to robustly test the interplay between extrinsic and intrinsic drivers of extinction under extreme climate change scenarios. We present the first integrated approach examining the role of potential intrinsic and extrinsic drivers in mediating extinction risk over the past 485 million years using state-of-the-art climate models to reconstruct physiological traits and localized climate change. We found that geographic range size, body size, realized thermal preference, realized niche breadth, and the magnitude of climate change are all necessary to predict extinction risk for taxa. Our results suggest that taxa previously identified as extinction resistant may still succumb to extinction if the magnitude of climate change is great enough.