Wildfires are becoming an increasing threat to many communities worldwide. There has been substantial progress towards understanding the proximal causes of increased fire activity in recent years at regional and national scales. However, subcontinental scale examinations of the commonalities and differences in the drivers of fire activity across different regions are rare in the Mediterranean zone of the European Union (EUMed). Here, we first develop a new classification of EUMed pyroregions, based on grouping different ecoregions with similar seasonal patterns of burned area. We then examine the thresholds associated with fire activity in response to different drivers related to fuel moisture, surface meteorology and atmospheric stability. We document an overarching role for variation in dead fuel moisture content (FMd), or its atmospheric proxy of vapor pressure deficit (VPD), as the major driver of fire activity. A proxy for live fuel moisture content (EVI), wind speed (WS) and the Continuous Haines Index (CH) played secondary, albeit important, roles. There were minor differences in the actual threshold values of FMd (10–12%), EVI (0.29–0.36) and CH (4.9–5.5) associated with the onset of fire activity across pyroregions with peak fire seasons in summer and fall, despite very marked differences in mean annual burned area and fire size range. The average size of fire events increased with the number of drivers exceeding critical thresholds and reaching increasingly extreme values of a driver led to disproportionate increases in the likelihood of a fire becoming a large fire. For instance, the percentage of fires >500 ha increased from 2% to 25% as FMd changed from the wettest to the driest quantile. Our study is among the first to jointly address the roles of fuel moisture, surface meteorology and atmospheric stability on fire activity in EUMed and provides novel insights on the interactions across fire activity triggers.