Water and soil salinity continuously rises due to climate change and irrigation with reused waters. Guayule (Parthenium argentatum A. Gray) is a desert perennial shrub native to northern Mexico and the southwestern United States; it is known worldwide for rubber production and is suitable for cultivation in arid and semiarid regions, such as the Mediterranean. In the present study, we investigated the effects of high and increasing concentrations of sodium chloride (NaCl) on the growth and the morphophysiological and biochemical characteristics of guayule to evaluate its tolerance to salt stress and suitability in phytomanagement and, eventually, the phytodesalinisation of salt-affected areas. Guayule originates from desert areas, but has not been found in salt-affected soils; thus, here, we tested the potential tolerance to salinity of this species, identifying the toxicity threshold and its possible sodium (Na) accumulation capacity. In a hydroponic floating root system, guayule seedlings were subjected to salinity-tolerance tests using increasing NaCl concentrations (from 2.5 to 40 g L−1 and from 43 to 684 mM). The first impairments in leaf morphophysiological traits appeared after adding 15 g L−1 (257 mM) NaCl, but the plants survived up to the hypersaline conditions of 35–40 g L−1 NaCl (about 600 mM). The distribution of major cell cations modulated the high Na content in the leaves, stems and roots; Na bioconcentration and translocation factors were close to one and greater than one, respectively. This is the first study on the morphophysiological and (bio)chemical response of guayule to different high and increasing levels of NaCl, showing the parameters and indices useful for identifying its salt tolerance threshold, adaptative mechanisms and reclamation potential in high-saline environments.