Over the past several decades, growth declines and mortality of trembling aspen throughout western Canada and the United States have been linked to drought, often interacting with outbreaks of insects and fungal pathogens, resulting in a “sudden aspen decline” throughout much of aspen’s range. In 2015, we noticed an aggressive fungal canker causing widespread mortality of aspen throughout interior Alaska and initiated a study to quantify potential drivers for the incidence, virulence, and distribution of the disease. Stand-level infection rates among 88 study sites distributed across 6 Alaska ecoregions ranged from <1 to 69%, with the proportion of trees with canker that were dead averaging 70% across all sites. The disease is most prevalent north of the Alaska Range within the Tanana Kuskokwim ecoregion. Modeling canker probability as a function of ecoregion, stand structure, landscape position, and climate revealed that smaller-diameter trees in older stands with greater aspen basal area have the highest canker incidence and mortality, while younger trees in younger stands appear virtually immune to the disease. Sites with higher summer vapor pressure deficits had significantly higher levels of canker infection and mortality. We believe the combined effects of this novel fungal canker pathogen, drought, and the persistent aspen leaf miner outbreak are triggering feedbacks between carbon starvation and hydraulic failure that are ultimately driving widespread mortality. Warmer early-season temperatures and prolonged late summer drought are leading to larger and more severe wildfires throughout interior Alaska that are favoring a shift from black spruce to forests dominated by Alaska paper birch and aspen. Widespread aspen mortality fostered by this rapidly spreading pathogen has significant implications for successional dynamics, ecosystem function, and feedbacks to disturbance regimes, particularly on sites too dry for Alaska paper birch.