The past 2500 years were marked by major historical developments across the eastern Mediterranean, the Middle East, the Arabian Peninsula, and the Nile Basin from Lake Victoria to the Nile Delta. Modeling efforts by both the global and regional climate modeling communities remain limited in this region. Here, we address this gap by presenting the first transient regional climate simulation for the area spanning 2350 years, from 500 BCE to 1850 CE, using the COSMO-CLM model. The simulation reveals an exceptionally pronounced climatic response to the consecutive volcanic eruptions of 536 and 540 CE, which motivated an additional century-long ensemble experiment to investigate this interval in greater detail. The eruptions produce marked surface cooling through reduced incoming solar radiation and are accompanied by large-scale circulation anomalies. In the simulation, widespread cooling persists until around 550 CE, with boreal summers showing the strongest anomalies during the first two to three years after the eruptions. Precipitation responses display strong regional contrasts: anomalously wet conditions occur over the Mediterranean, the Middle East, and Southeast Africa, particularly during the climatologically dry Northern Hemisphere summer season, whereas the Sahara, the Arabian Peninsula, Central Africa, and Northeast Africa experience concurrent dryness concentrated in their respective rainy seasons. The most severe climatic anomalies occur within the first one to two years after the eruptions and gradually weaken over the following years.