Haloxylon ammodendronandHaloxylon persicum, as typical desert plants in arid areas, show strong drought tolerance and environmental adaptability and are therefore ideal model plants for studying the molecular mechanisms of drought tolerance. A metabolomic analysis ofH. ammodendronandH. persicumin their natural environment is lacking, and their metabolic response to drought therefore remains unclear. To elucidate the response ofH. ammodendronandH. persicumto drought at the metabolic level, a non-targeted metabolomics analysis was carried out herein. Under a dry environment,H. ammodendronexhibited 296 and 252 differentially expressed metabolites (DEMs) in the positive and negative ion modes, respectively, whereas 452 and 354 DEMs were identified in the positive and negative ion modes inH. persicum, respectively. The results indicated thatH. ammodendronresponds to drought by increasing the content of organic nitrogen compounds and lignans, neolignans, and related compounds, and reducing the content of alkaloids and derivatives. By contrast,H. persicumadapts to the dry environment by increasing the content of organic acids and their derivatives and reducing the content of lignans, neolignans, and related compounds. In addition,H. ammodendronandH. persicumimproved their osmoregulation ability, reactive oxygen species detoxification ability, and cell membrane stability by regulating the key metabolic pathways and anabolism of associated metabolites. This is the first metabolomics report on the response ofH. ammodendronandH. persicumto drought in their natural environment, providing a foundation for the further study of their regulatory mechanisms under drought stress.