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The East Alashan–Ordos Dryland of Inner Mongolia, China is the core area of the South Mongolian region, and one of the eight biodiversity centers in China. The plant biodiversity in the East Alashan–Ordos Dryland is diverse and unique, but its distribution and characteristics are yet to be well understood. Our results indicate that there are 5 endemic genera (Tetraena, Potaninia, Tugarinovia, Stilpnolepis, and Pugionium) and 2 Central Asian desert endemic genera (Ammopiptanthus and Elachanthemum) in this region. These 7 local and semi-local endemic genera are all distributed in plain or piedmont areas. There are 92 species and 18 varieties of local and semi-local endemic species of seed plants, accounting for 11.3% of all seed plants in this area. Eleven species are associated with endemic communities that are found in the Helan mountainous area and plain or piedmont areas. The flora of this region is a mix of both ancient and young species and exhibits clear spatial differentiation. Most endemic taxonomic groups in the plains are considered to originate from old arid regions, whereas endemic taxonomic groups in the mountains are considered to have formed through recent differentiation. The area has a rich xeric biota in which the xeric types account for 45% of all mountainous endemic plants as well as 78% of all plain endemic plants. Our study provides the first comprehensive, occurrence-based synthesis of endemic plant diversity and spatial differentiation in the East Alashan–Ordos Dryland, highlighting its long under-appreciated conservation value.