Fire is a key driver of ecosystem dynamics under global change, and understanding its complex relationship with the climate system is crucial for regional wildfire risk management and the development of ecological adaptation strategies. The western United States is a critical region for studying fire–climate interactions due to its pronounced environmental gradients, diverse fire regimes, and high vulnerability to climate change, which together provide a robust natural laboratory for examining spatial variability in fire responses. Based on tree-ring fire-scar records systematically collected from five major ecoregions in the western United States via the International Tree-Ring Data Bank (ITRDB), this study reconstructed fire history sequences spanning 430–454 years. By integrating methods such as correlation analysis, random forest regression, superposed epoch analysis, and effect size assessment, we systematically revealed the spatial differentiation patterns of fire frequency and fire spatial extent across different ecoregions, quantified the relative contributions of key climatic drivers, and identified climatic anomaly characteristics during extreme fire years. The results indicate that: (1) there are significant differences in fire frequency between different ecological areas; (2) summer drought conditions (PDSI) are the most consistent and strongest driver of fire across all ecoregions, and ENSO (NINO3) also shows a widespread negative correlation; (3) random forest models indicate that the Sierra Nevada and Madrean Archipelago ecoregions are the most sensitive to multiple climatic factors, while fire in regions such as the Northern Rockies may be more regulated by non-climatic processes; (4) extreme fire years across all ecoregions are associated with significant negative PDSI anomalies with prominent effect sizes, confirming that severe drought is the dominant cross-regional precondition for extreme fire events. This study emphasizes the region-specific nature of fire–climate relationships and provides a scientific basis for developing differentiated, ecoregion-specific fire prediction models and prevention strategies. The methodological framework and findings offer valuable insights for fire regime studies in other global forest ecosystems facing similar climate challenges.