Hydroclimatic variability is expected to be affected by global warming in the Mediterranean region where climate, fire and human activities are known to be interdependent. The latter is examined here for the past millennium by studying paleoenvironmental indicators from a sedimentary sequence at Lagunillo del Tejo (Cuenca, central Spain). Inferred changes in fire activity and lake levels are based on records of macrocharcoals and plant/algal macrofossils, respectively, and are compared with independent information on climate change and socio-economical transformations from historical and meteorological records. The results show that there is an obvious climatic forcing behind the lake-level changes recorded at Lagunillo del Tejo, and a good correlation between the periods of high fire activity/frequent fires and low lake level/drought conditions. The reconstructed fire regime may therefore be natural (climate-induced), but can also be explained by important socio-economical events/changes, including wars and the introduction of the Transhumance practices (ad 1273). There is a good chronological agreement between lowest fire activity and high lake levels (c. ad 1600–1800), concurrent with the late ‘Little Ice Age’ (LIA) and the collapse of the Transhumance system. We propose that periods of drought favored both natural and human-induced fires during the ‘Medieval Climatic Anomaly’ (around ad 1200), at the start of the LIA (around ad 1400), in the middle of the LIA (sixteenth century) and during the entire nineteenth century. This record is an example of long-term interplay between climate changes and human activities and its impact on environmental changes such as fire regimes.