Drought-induced tree mortality is occurring across all forested continents and is expected to increase worldwide during the coming century. Regional-scale forest die-off influences terrestrial albedo, carbon and water budgets, and land-surface energy partitioning. Although increased temperatures during drought are widely identified as a critical contributor to exacerbated tree mortality associated with “global-change-type drought”, corresponding changes in vapor pressure deficit (D) have rarely been considered explicitly and have not been disaggregated from that of temperature per se. Here, we apply a detailed mechanistic soil–plant–atmosphere model to examine the impacts of drought, increased air temperature (+2°C or +5°C), and increased vapor pressure deficit (D; +1 kPa or +2.5 kPa), singly and in combination, on net primary productivity (NPP) and transpiration and forest responses, especially soil moisture content, leaf water potential, and stomatal conductance. We show that increased D exerts a larger detrimental effect on transpiration and NPP, than increased temperature alone, with or without the imposition of a 3-month drought. Combined with drought, the effect of increased D on NPP was substantially larger than that of drought plus increased temperature. Thus, the number of days when NPP was zero across the 2-year simulation was 13 or 14 days in the control and increased temperature scenarios, but increased to approximately 200 days when D was increased. Drought alone increased the number of days of zero NPP to 88, but drought plus increased temperature did not increase the number of days. In contrast, drought and increased D resulted in the number of days when NPP = 0 increasing to 235 (+1 kPa) or 304 days (+2.5 kPa). We conclude that correct identification of the causes of global change-type mortality events requires explicit consideration of the influence of D as well as its interaction with drought and temperature.