The Akkadian empire ruled Mesopotamia from the headwaters of the Tigris-Euphrates Rivers to the Persian Gulf during the late third millennium B.C. Archeological evidence has shown that this highly developed civilization collapsed abruptly near 4170 ± 150 calendar yr B.P., perhaps related to a shift to more arid conditions. Detailed paleoclimate records to test this assertion from Mesopotamia are rare, but changes in regional aridity are preserved in adjacent ocean basins. We document Holocene changes in regional aridity using mineralogic and geochemical analyses of a marine sediment core from the Gulf of Oman, which is directly downwind of Mesopotamian dust source areas and archeological sites. Our results document a very abrupt increase in eolian dust and Mesopotamian aridity, accelerator mass spectrometer radiocarbon dated to 4025 ± 125 calendar yr B.P., which persisted for ∼300 yr. Radiogenic (Nd and Sr) isotope analyses confirm that the observed increase in mineral dust was derived from Mesopotamian source areas. Geochemical correlation of volcanic ash shards between the archeological site and marine sediment record establishes a direct temporal link between Mesopotamian aridification and social collapse, implicating a sudden shift to more arid conditions as a key factor contributing to the collapse of the Akkadian empire.