Fire is a natural component of global biogeochemical cycles and closely related to changes in human land use. Whereas climate-fuel relationships seem to drive both global and subcontinental fire regimes, human-induced fires are prominent mainly on a local scale. Furthermore, the basic assumption that relates humans and fire regimes in terms of population densities, suggesting that few human-induced fires should occur in periods and areas of low population density, is currently debated. Here, we analyze human-fire relationships throughout the Holocene and discuss how and to what extent human-driven fires affected the landscape transformation in the Central European Lowlands (CEL). We present sedimentary charcoal composites on three spatial scales and compare them with climate model output and land cover reconstructions from pollen records. Our findings indicate that widespread natural fires only occurred during the early Holocene. Natural conditions (climate and vegetation) limited the extent of wildfires beginning 8500 cal. BP, and diverging subregional charcoal composites suggest that Mesolithic hunter-gatherers maintained a culturally diverse use of fire. Divergence in regional charcoal composites marks the spread of sedentary cultures in the western and eastern CEL. The intensification of human land use during the last millennium drove an increase in fire activity to early-Holocene levels across the CEL. Hence, humans have significantly affected natural fire regimes beyond the local scale - even in periods of low population densities - depending on diverse cultural land-use strategies. We find that humans have strongly affected land-cover- and biogeochemical cycles since Mesolithic times.