Climate change and water availability in the Middle East are important in understanding human adaptive capacities in the face of long-term environmental changes. The key role of water availability for sedentary and nomad populations in these arid to semiarid landscapes is understood, but the millennium-scale influence of hydrologic instability on vegetation dynamics, human occupation, and historic land use are unknown, which has led to a stochastic view of population responses and adaptive capacities to precipitation anomalies. Within the time-frame of the last two global climate events, the Medieval Climate Anomaly and the Little Ice Age, we report hydrologic instability reconstructed from pollen-derived climate proxies recovered near Tell Leilan, at the Wadi Jarrah in the Khabur Plains of northeastern Syria, at the heart of ancient northern Mesopotamia. By coupling climate proxies with archaeological-historical data and a pollen-based record of agriculture, this integrative study suggests that variability in precipitation is a key factor on crop yields, productivity, and economic systems. It may also have been one of the main parameters controlling human settlement and population migrations at the century to millennial timescales in the arid to semiarid areas of the Middle East. An abrupt shift to drier conditions at ca. AD 1400 is contemporaneous with a change from sedentary village life to regional desertion and nomadization (sheep/camel pastoralists) during the preindustrial era in formerly Ottoman realms, and thereby adds climate change to the multiple causes for Ottoman Empire "decline."