Gypsum endemics (i.e. gypsophiles) have adapted to live in gypsum-rich soils where nutrient unbalance and drought can be extreme. Despite their relevance as plants adapted to extreme conditions, a complete analysis of the physiological responses of gypsophiles to drought is still lacking. Helianthemum squamatum (L.) Dum. Cours. is a conspicuous Iberian gypsophile that has been reported to use gypsum crystallization water during the driest period, but the mechanisms behind this process are unknown. To characterize gypsophile responses to drought and unravel the mechanisms underlying gypsum crystalline water use, H. squamatum plants were grown in pots with natural gypsum soil and gypsum soil with deuterium-labelled crystalline water. After three years, a drought experiment was carried out and whole-plant responses were investigated. Unexpectedly, the labelling treatment affected soil physicochemical characteristics and reduced microbial biomass and organic matter content, decreasing plant aerial biomass. H. squamatum plants did not use gypsum crystallization water during simulated drought neither in the labelled soil, nor in the natural one. Drought reduced plant transpiration, stomatal conductance, water use, photosynthetic rate and the foliar concentration of most elements except P and N, which were higher in the drought stressed plants. We detected increased root exudation of choline, an osmoprotector, by drought stressed plants. The drought treatment also affected the structure of microbial communities but did not reduce the relative abundance of functional microbial groups, highly adapted to the natural drought pulses. Our results highlight an integrated water-saving strategy of H. squamatum plants in the short-term, where responses at the leaf level are combined with belowground processes, like altered root exudation. Our findings also underline the remarkable resistance to drought of microbial communities present in gypsum soils.