Sustained human pressures on the environment have significantly increased the frequency, extent, and severity of wildfires, globally. This is particularly the case in Mediterranean regions, in which human-caused wildfires represent up to 90% of all recorded wildfire ignitions. In Chile, it has been estimated that nearly 90% of wildfires are related to human activities, and that their frequency and distribution have steadily increased over the last decade. Despite this, the role of socio-economic factors in driving wildfire activity and its spatiotemporal distribution remains unclear. In this study, we assess the association between socio-economic drivers and spatiotemporal patterns of wildfires in the Mediterranean region of south-central Chile over the period 2010–2018. Our results show that 98.5% of wildfires are related to human activities, either accidentally (58.2%) or intentionally (36.6%). Wildfires occurred primarily during the summer months and their density at the commune-level was associated with increased road access, as well as with the percentage of land covered by agriculture, exotic tree plantations, and native forest. Wildfire activity at the commune-level was also related to socio-economic variables such as population density, proportion of indigenous population, and unemployment rate, although such associations varied considerably depending on the region and on whether the wildfire was started accidentally or intentionally. Our study provides a comprehensive and interdisciplinary assessment of the complex ways in which land-cover and socio-economic factors drive the distribution of wildfire activity in south-central Chile. It represents an important guide for policy-making, as well a baseline for research into strategies aimed at predicting and mitigating wildfire activity at both local and national levels.