The Mediterranean–Red Sea region has been critical to dispersal of hominids and other species between Africa and the rest of the world, and climate and sea level are thought to be key controls on migration pathways. Assessing climate variations, we highlight increased millennial-scale variability at 480–460, 440–400, 380–360, 340–320, 260–220, 200–160, 140–120, and 80–40 thousand years ago (ka), which likely caused intermittent habitat fragmentation. We also find that passageways across the Sahara Desert and the northern out-of-Africa route (from Egypt into the Levant) were intermittently open during pluvials associated with orbital insolation maxima. No such relationship is apparent for the southern out-of-Africa route (across the Red Sea). Instead, we present a novel interpretation of combined sea-level and regional climate control on potential migrations via the southern route, with “windows of opportunity” at 458–448, 345–340, 272–265, 145–140, and 70–65 ka. The 145–140 ka window seems relevant for early colonization of Arabia at 127 ± 16 ka, and the 70–65 ka window agrees with estimates of 65 +5/−8 ka for the final out-of-Africa migration by the anatomically modern human founder group of all non-Africans. Once they reached Eurasian Mediterranean margins, populations benefited from a rich diversity of terrain and microclimates, with persistent favorable conditions in lowlands and potential to occupy higher elevations during milder periods.