Climate change is expected to significantly increase drought severity in the American Southwest and Central Plains by the end of the 21st century. Using empirical drought reconstructions and soil moisture metrics from 17 general circulation models (GCMs), the study shows that these models project significantly drier conditions in the latter half of the 21st century compared to the 20th century and earlier paleoclimatic intervals. This drying trend is consistent across most models and moisture balance variables, indicating a robust response to warming. Future drought risk is likely to exceed even the driest centuries of the Medieval Climate Anomaly (1100–1300 CE) in both moderate (RCP 4.5) and high (RCP 8.5) emissions scenarios, leading to unprecedented drought conditions during the last millennium. The study compares 21st-century drought projections from GCMs with the paleo-record, highlighting the need to place these projections within the context of long-term drought variability. The Palmer Drought Severity Index (PDSI) is used as a key metric, which is a locally normalized index of soil moisture availability. While PDSI is widely used for drought monitoring, concerns exist about its ability to accurately reflect surface moisture balance in GCMs. The study uses a more physically based version of PDSI in conjunction with soil moisture from GCMs to demonstrate robust drought responses to climate change in the Central Plains and Southwest regions of Western North America. Results show that the multimodel mean indicates consistent drying in the later half of the 21st century, with the Southwest experiencing more severe drying than the Central Plains. The drying is primarily driven by increased evaporative demand due to warming, rather than changes in ocean-atmosphere dynamics. In the Central Plains, the drying is driven by increased evaporative demand, while in the Southwest, it is due to reduced cold season precipitation and increased evaporative demand. The study also finds that the risk of decadal or multidecadal drought occurrences is significantly higher in the 21st century compared to the historical period, with a high probability of a multidecadal drought in the Central Plains and Southwest under the RCP 8.5 scenario. The study concludes that the risk of a multidecadal megadrought in the Central Plains and Southwest during the late 21st century is exceptionally high, exceeding even the persistent megadroughts of the Medieval era. This highlights the need for adaptation strategies to manage water resources and ecosystems in the face of increased drought risk.Climate change is expected to significantly increase drought severity in the American Southwest and Central Plains by the end of the 21st century. Using empirical drought reconstructions and soil moisture metrics from 17 general circulation models (GCMs), the study shows that these models project significantly drier conditions in the latter half of the 21st century compared to the 20th century and earlier paleoclimatic intervals. This drying trend is consistent across most models and moisture balance variables, indicating a robust response to warming. Future drought risk is likely to exceed even the driest centuries of the Medieval Climate Anomaly (1100–1300 CE) in both moderate (RCP 4.5) and high (RCP 8.5) emissions scenarios, leading to unprecedented drought conditions during the last millennium. The study compares 21st-century drought projections from GCMs with the paleo-record, highlighting the need to place these projections within the context of long-term drought variability. The Palmer Drought Severity Index (PDSI) is used as a key metric, which is a locally normalized index of soil moisture availability. While PDSI is widely used for drought monitoring, concerns exist about its ability to accurately reflect surface moisture balance in GCMs. The study uses a more physically based version of PDSI in conjunction with soil moisture from GCMs to demonstrate robust drought responses to climate change in the Central Plains and Southwest regions of Western North America. Results show that the multimodel mean indicates consistent drying in the later half of the 21st century, with the Southwest experiencing more severe drying than the Central Plains. The drying is primarily driven by increased evaporative demand due to warming, rather than changes in ocean-atmosphere dynamics. In the Central Plains, the drying is driven by increased evaporative demand, while in the Southwest, it is due to reduced cold season precipitation and increased evaporative demand. The study also finds that the risk of decadal or multidecadal drought occurrences is significantly higher in the 21st century compared to the historical period, with a high probability of a multidecadal drought in the Central Plains and Southwest under the RCP 8.5 scenario. The study concludes that the risk of a multidecadal megadrought in the Central Plains and Southwest during the late 21st century is exceptionally high, exceeding even the persistent megadroughts of the Medieval era. This highlights the need for adaptation strategies to manage water resources and ecosystems in the face of increased drought risk.