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Drought is projected to become more severe and widespread as global warming continues in the twenty-first century, but hydroclimatic changes and their drivers are not well examined in the latest projections from phase 6 of the Coupled Model Intercomparison Project (CMIP6). Here, precipitation (P), evapotranspiration (E), soil moisture (SM), and runoff (R) from 25 CMIP6 models, together with self-calibrated Palmer drought severity index with Penman–Monteith potential evapotranspiration (scPDSIpm), are analyzed to quantify hydroclimatic and drought changes in the twenty-first century and the underlying causes. Results confirm consistent drying in these hydroclimatic metrics across most of the Americas (including the Amazon), Europe and the Mediterranean region, southern Africa, and Australia, although the drying magnitude differs, with the drying being more severe and widespread in surface SM than in total SM. Global drought frequency based on surface SM and scPDSIpm increases by ∼25%–100% (50%–200%) under the SSP2-4.5 (SSP5-8.5) scenario in the twenty-first century together with large increases in drought duration and areas, which result from a decrease in the mean and flattening of the probability distribution functions of SM and scPDSIpm, while the R-based drought changes are relatively small. Changes in both P and E contribute to the SM change, whereas scPDSIpm decreases result from ubiquitous PET increases and P decreases over subtropical areas. The R changes are determined primarily by P changes, while the PET change explains most of the E increase. Intermodel spreads in surface SM and R changes are large, leading to large uncertainties in the drought projections. SIGNIFICANCE STATEMENT: Drought may become more severe and widespread under greenhouse gas (GHG)-induced global warming in the twenty-first century based on model projections. However, there are still large uncertainties in projected future drought changes, especially regarding the extent to which drought changes depend on drought indices and the future emissions scenarios analyzed. The latest projections from CMIP6 models reaffirm the widespread drying and increases in agricultural drought by up to 200% over most of the Americas (including the Amazon), Europe and the Mediterranean region, southern Africa, Southeast Asia, and Australia under moderate-to-high emissions scenarios in the twenty-first century, despite large uncertainties in individual projections partly due to internal variability. Ubiquitous increases in atmospheric demand for moisture under rising temperatures and precipitation decreases over many subtropical regions are the main driver of the projected drying and drought increases. [ABSTRACT FROM AUTHOR]