Evaluating the impact and implications of eolian repositories that mark large-scale climatic transitions requires knowledge about the timing of their emplacement and the mechanisms responsible for their production, which remain highly uncertain. Here we apply numerical modeling of cosmogenic nuclide data, measured in the largest continuous terrestrial body of sand on Earth, to determine settings under which the sand was generated, by constraining the timing of sand introduction into the interior of southern Africa. Our findings reveal that major events of sand formation and accumulation in the Kalahari Basin occurred between ~2.2 and 1 Myr ago. The establishment of the Kalahari sand field corresponds to regional, continental, and global scale morphotectonic and climatic changes that contributed to the mass production and widespread dispersion of sand. These changes substantially altered existing habitats, thus constituting a crucial milestone for flora, fauna, and hominins in southern Africa during the Pleistocene.