Several large-scale drivers of both anthropogenic and natural environmental changes are interacting nonlinearly in the transition zone between eastern Amazonia and the adjacent Cerrado, considered to be another Brazilian agricultural frontier. Land-use change for agrobusiness expansion together with climate change in the transition zone between eastern Amazonia and the adjacent Cerrado may have induced a worsening of severe drought conditions over the last decade. Here we show that the largest warming and drying trends over tropical South America during the last four decades are observed to be precisely in the eastern Amazonia–Cerrado transition region, where they induce delayed wet-season and worsen severe drought conditions over the last decade. Our results evidence an increase in temperature, vapor pressure deficit, subsidence, dry-day frequency, and a decrease in precipitation, humidity, and evaporation, plus a delay in the onset of the wet season, inducing a higher risk of fire during the dry-to-wet transition season. These findings provide observational evidence of the increasing climatic pressure in this area, which is sensitive for global food security, and the need to reconcile agricultural expansion and protection of natural tropical biomes.