Deforestation is currently the major threat to Amazonian tree species but climate change may surpass it in just a few decades. Here, we show that climate and deforestation combined could cause a decline of up to 58% in Amazon tree species richness, whilst deforestation alone may cause 19–36% and climate change 31–37% by 2050. Quantification is achieved by overlaying species distribution models for current and future climate change scenarios with historical and projected deforestation. Species may lose an average of 65% of their original environmentally suitable area, and a total of 53% may be threatened according to IUCN Red List criteria; however, Amazonian protected area networks reduce these impacts. The worst-case combined scenario—assuming no substantial climate or deforestation policy progress—suggests that by 2050 the Amazonian lowland rainforest may be cut into two blocks: one continuous block with 53% of the original area and another severely fragmented block. This outlook urges rapid progress to zero deforestation, which would help to mitigate climate change and foster biodiversity conservation.