Durum wheat is still the main cereal crop, both in rainfed and irrigated. However, soil and irrigation water salinity remain the main abiotic factors limiting its productivity, especially in arid and semi-arid environments driven by climate change. Understanding the mechanisms by which plants respond and adapt to salinity would enable the selection of tolerant cultivars and identify useful traits and markers of tolerance. Accordingly, a greenhouse experiment was conducted on four cultivars of durum wheat (Triticum durum Desf.) subjected to salinity stress. Physio-biochemical parameters (growth, water relations, gas exchange, chlorophyll pigments, ionic content, and endogenous phytohormones) and their interrelationships were analyzed. Obtained results showed that salt stress affects plant growth, chlorophyll pigments, photosynthetic parameters and growth hormones, promote the accumulation of sodium at the expense of potassium, disrupts water relations, and stimulates stress hormones. These metabolic changes remain strictly cultivar-dependent, while Karim proved less vulnerable to salt stress. The relative tolerance of durum wheat to salinity stress depends closely on its ability to regulate water relations through osmotic adjustment and optimization of photosynthetic parameters. Although growth hormones have been affected, stress hormones are stimulated and appear to play a key role in stress signaling, modulation of ionic compartmentalization through promoted K uptake, and stimulation of osmolyte accumulation. These two mechanisms help preserve gas exchange and maintain net photosynthetic assimilation, leading to improved biomass production.