Global temperature rise and extremes accompanying drought threaten forests and their associated climatic feedbacks. Our ability to accurately simulate drought-induced forest impacts remains highly uncertain in part owing to our failure to integrate physiological measurements, regional-scale models, and dynamic global vegetation models (DGVMs). Here we show consistent predictions of widespread mortality of needleleaf evergreen trees (NET) within Southwest USA by 2100 using state-of-the-art models evaluated against empirical data sets. Experimentally, dominant Southwest USA NET species died when they fell below predawn water potential (Ψ_pd) thresholds (April–August mean) beyond which photosynthesis, hydraulic and stomatal conductance, and carbohydrate availability approached zero. The evaluated regional models accurately predicted NET Ψ_pd, and 91% of predictions (10 out of 11) exceeded mortality thresholds within the twenty-first century due to temperature rise. The independent DGVMs predicted ≥50% loss of Northern Hemisphere NET by 2100, consistent with the NET findings for Southwest USA. Notably, the global models underestimated future mortality within Southwest USA, highlighting that predictions of future mortality within global models may be underestimates. Taken together, the validated regional predictions and the global simulations predict widespread conifer loss in coming decades under projected global warming.