Since fire has been recognized as an essential disturbance in Mediterranean landscapes, the study of long-term fire ecology has developed rapidly. We have reconstructed a sequence of vegetation dynamics and fire changes across south-eastern Iberia by coupling records of climate, fire, vegetation and human activities. We calculated fire activity anomalies (FAAs) in relation to 3 ka cal BP for 10–8 ka cal BP, 6 ka cal BP, 4 ka cal BP and the present. For most of the Early to the Mid-Holocene uneven, but low fire events were the main vegetation driver at high altitudes where broadleaved and coniferous trees presented a highly dynamic post-fire response. At mid-altitudes in the mainland Segura Mountains, fire activity remained relatively stable, at similar levels to recent times. We hypothesize that coastal areas, both mountains and lowlands, were more fire-prone landscapes as biomass was more likely to have accumulated than in the inland regions, triggering regular fire events. The wet and warm phase towards the Mid-Holocene (between ca 8 and 6 ka cal BP) affected the whole region and promoted the spread of mesophytic forest co-existing with Pinus, as FAAs appear strongly negative at 6 ka cal BP, with a less important role of fire. Mid and Late Holocene landscapes were shaped by an increasing aridity trend and the rise of human occupation, especially in the coastal mountains where forest disappeared from ca 2 ka cal BP. Mediterranean-type vegetation (evergreen oaks and Pinus pinaster-halepensis types) showed the fastest post-fire vegetation dynamics over time.