Global change includes multiple stressors to natural ecosystems ranging from direct climate and land-use impacts to indirect degradation processes resulting from fire. Humid tropical forests are vulnerable to projected climate change and possible synergistic interactions with deforestation and fire, which may initiate a positive feedback to rising atmospheric CO2. Here, we present results from a multifactorial impact analysis that combined an ensemble of climate change models with feedbacks from deforestation and accidental fires to quantify changes in Amazon Basin carbon cycling. Using the LPJmL Dynamic Global Vegetation Model, we modelled spatio-temporal changes in net biome production (NBP); the difference between carbon fluxes from fire, deforestation, soil respiration and net primary production. By 2050, deforestation and fire (with no CO2 increase or climate change) resulted in carbon losses of 7.4–20.3 Pg C with the range of uncertainty depending on socio-economic storyline. During the same time period, interactions between climate and land use either compensated for carbon losses due to wetter climate and CO2 fertilization or exacerbated carbon losses from drought-induced forest mortality (−20.1 to +4.3 Pg C). By the end of the 21st century, depending on climate projection and the rate of deforestation (including its interaction with fire), carbon stocks either increased (+12.6 Pg C) or decreased (−40.6 Pg C). The synergistic effect of deforestation and fire with climate change contributed up to 26–36 Pg C of the overall decrease in carbon stocks. Agreement between climate projections (n=9), not accounting for deforestation and fire, in 2050 and 2098 was relatively low for the directional change in basin-wide NBP (19–37%) and aboveground live biomass (13–24%). The largest uncertainty resulted from climate projections, followed by implementation of ecosystem dynamics and deforestation. Our analysis partitions the drivers of tropical ecosystem change and is relevant for guiding mitigation and adaptation policy related to global change.