The Middle East is one of the world’s most vulnerable areas to climate change, which has exacerbated environmental, agricultural, water conflict, and public health issues in the region. Here we analyze the latest climate model projections of precipitation and temperature for the very high emissions scenario, SSP5-8.5, to detect potential future changes in this region. A baseline period (1981-2010) is compared with the middle (2040-2069) and end (2070-2099) of the 21^st century. The results, representing the worst-case scenario, identify the Tigris-Euphrates headwaters as the hotspot of future compounding effects of climate change in the Middle East. Those effects result from the coincidence of elevated temperature, reduced precipitation, and enhanced interannual variability of precipitation. The hotspot overlays the location of the Southeastern Anatolia Project (in Turkish, GAP) irrigation initiative. In this climate context, risks to GAP viability and downstream water security, and associated potential for water-related conflicts and migration are considerable and demand a reconsideration of the risk-benefit assessment of GAP. This need has become more urgent after the recent widespread and deadly climate-related conflicts and wildfires in summer 2021 across the Middle East that further underlined vulnerability of the region to climate extremes.