Aim The anthropogenic climate change and land use change are considered two of the main factors that are altering biodiversity at the global scale. An evaluation that combined both factors can be relevant to detect which species could be the most vulnerable and reveal the regions of highest stability or susceptibility to biodiversity. We aimed to: (a) assess the effect of climate change and land use on the distribution of Cerrado plant species for different countries where they occur, (b) evaluate the effectiveness of the current network of protected areas (PAs) to safeguards species under different greenhouse-gas (GHG) emissions and land use scenarios, and (c) estimate the vulnerability of species based on protection effectiveness and habitat loss. Location Bolivia, Brazil and Paraguay. Methods We modelled the distribution of 1,553 plant species of Cerrado and evaluated species range loss caused by present and future land use and two GHG for 2050 and 2080. We assessed species vulnerability combining the representativeness of species within conservation units with the loss of species’ ranges outside PAs. Results We found that climate change and land use will cause great damage to Cerrado flora by 2050 and 2080, even under optimistic conditions. The greatest impacts of land use will occur in the regions where the greatest richness will be harboured. The conservation of the species will be seriously affected since the PA network is not as effective in safeguarding them under current or future conditions. Main conclusions The low level of protection together with the losses caused by the advance of agricultural lands will lead most species being highly vulnerable. Due to the distinct impacts of climate and land use over the three countries, conservation strategies should be implemented at transboundary and national levels.