Tibetan wheat is grown under environmental constraints at high-altitude conditions, but its underlying adaptation mechanism remains unknown. Here, we present a draft genome sequence of a Tibetan semi-wild wheat (Triticum aestivum ssp. tibetanum Shao) accession Zang1817 and re-sequence 245 wheat accessions, including world-wide wheat landraces, cultivars as well as Tibetan landraces. We demonstrate that high-altitude environments can trigger extensive reshaping of wheat genomes, and also uncover that Tibetan wheat accessions accumulate high-altitude adapted haplotypes of related genes in response to harsh environmental constraints. Moreover, we find that Tibetan semi-wild wheat is a feral form of Tibetan landrace, and identify two associated loci, including a 0.8-Mb deletion region containing Brt1/2 homologs and a genomic region with TaQ-5A gene, responsible for rachis brittleness during the de-domestication episode. Our study provides confident evidence to support the hypothesis that Tibetan semi-wild wheat is de-domesticated from local landraces, in response to high-altitude extremes.