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Recognized as one of the richest and most extensive savannas in the world, the Cerrado region, the second largest biome in South America, presents an intense and continuous human-induced land-cover change, which has already affected around 40% of its original area. In the pursuit of orientation and planning for current and long-term occupation, in this work we present plausible deforestation scenarios for the entire Cerrado biome, to 2050. Based on integration of spatial variables, such as terrain slope, climate, and infrastructure, we applied a multivariate and nonlinear modeling technique for the location of deforestation, assuming a business-as-usual scenario. Our results indicate an increase of the deforested areas by 13.5% until 2050 (compared to 2002, our initial landscape map), at an average decadal conversion rate of 40,000 km². These potential landscape changes are more prominent in the biome’s northern and northeastern agricultural frontiers, where large land-use demands are expected, with direct impacts and threats to the region’s water resources, soil, and biodiversity.