Clearing tropical vegetation impacts biodiversity, the provision of ecosystem services, and thus ultimately human welfare. We quantified changes in land cover from 2000 to 2015 across the Cerrado biome of northern Minas Gerais state, Brazil. We assessed the potential biophysical and social-economic drivers of the loss of Cerrado, natural regeneration and net cover change at the municipality level. Further, we evaluated correlations between these land change variables and indicators of human welfare. We detected extensive land cover changes in the study area, with the conversion of 23,446 km2 and the natural regeneration of 13,926 km2, resulting in a net loss of 9,520 km2. The annual net loss (-1.2% per year) of the cover of Cerrado is higher than that reported for the whole biome in similar periods. We argue that environmental and economic variables interact to underpin rates of conversion of Cerrado, most severely affecting more humid Cerrado lowlands. While rates of Cerrado regeneration are important for conservation strategies of the remaining biome, their integrity must be investigated given the likelihood of encroachment. Given the high frequency of land abandonment in tropical regions, secondary vegetation is fundamental to maintain biodiversity and ecosystem services. Finally, the impacts of Cerrado conversion on human welfare likely vary from local to regional scales, making it difficult to elaborate land use policies based solely on social-economic indicators.