The dynamics of Amazonian rainforest over long timescales connects closely to its rich biodiversity. While palaeoecological studies have suggested its stability through the Pleistocene, palaeontological evidence indicates the past existence of major expansions of savanna and grassland. Here we present integrated modeling evidence for a grassier Neotropics during the Last Glacial Maximum (LGM), congruent with palaeoecological and biological studies. Vegetation re-constructions were generated using the Land Processes and eXchanges (LPX) model, driven by model reconstructions of LGM climate, and compared against palynological data. A factorial experiment was performed to quantify the impacts of fire and low CO2 on vegetation and model-data agreement. Fire and low CO2 both individually and interactively induced widespread expansion of savanna and grassland biomes while improving model-data agreement. The interactive effects of fire and low CO2 induced the greatest ‘savannafication’ of the Neotropics, providing integrated evidence for a number of biogeographically relevant open vegetation formations including two dry corridors; paths of savanna and grassland through and around Amazonia that facilitated major dispersal and evolutionary diversification events. Our results show a bimodality in tree cover that was driven by fire and further enhanced by ‘CO2 deprivation’, which suggests biome instability in this region of climate space.