We present a novel model for the formation and spatial and temporal evolution of topographic mega-depressions in the hyperarid Sahara Desert. The model is based on field observations, structural analysis, remote sensing data, and isotopic measurements of travertine deposits from the eastern Farafra Plateau in the Western Desert, Egypt. Four stages were identified: an initial stage coeval with the Cenozoic rifting in northeast Africa and three stages in the Pleistocene: (a) formation of depressions along fault zones as pull-apart basins and en echelon grabens within transtensional systems; (b) preferential growth of incipient depressions along faults due to groundwater sapping processes; (c) coalescence of depressions to form larger ones through degradation of escarpments and formation of intra-depression landforms; and (d) formation of deep mega-depressions through horizontal and vertical propagation of smaller depressions along the dominant structural grain. The growth of the mega-depressions was accompanied by the development of Theater-Headed Valleys along the escarpments of coalesced depressions, possibly due to groundwater-sapping processes. The proposed model is supported by the isotopic compositions of travertine in the depressions (delta 18OVSMOW = +17.9 to +19.7 %o), consistent with deposition from depleted Nubian Sandstone groundwater (delta 18OVSMOW = -8.0 to -12.8 %o). Findings include: (1) mega-depressions originate from numerous small, actively growing depressions coalescing into larger structures rather than a single depression retreating over time, (2) geological structures play a pivotal role in the genesis of nascent depressions through the localization and amplification of surface processes. The findings could enhance our understanding of the rates and temporal dynamics of depression formation elsewhere.