A majority of area burned in the Eastern United States (EUS) results from a limited number of exceptionally large wildfires. Relationships between climatic conditions and the occurrence of very large-fires (VLF) in the EUS were examined using composite and climate-niche analyses that consider atmospheric factors across inter-annual, sub-seasonal and synoptic temporal scales. While most large-fires in the EUS coincided with below normal fuel moisture and elevated fire weather, VLF preferentially occurred during a long-term drought accompanied by more acute sub-seasonal drought realized through fuel moisture stress and elevated fire-weather conditions. These results were corroborated across the EUS, with varying influences of drought, fire danger and fire weather discriminating VLF from other large fires across different geographical regions. We also show that the probability of VLF conditioned by fire occurrence increases when long-term drought, depleted fuel moisture and elevated fire weather align. This framework illustrates the compounding role of different timescales in VLF occurrence and serves as a basis for improving VLF predictions with seasonal climate forecasts and climate change scenarios.