Cereals are the most important nutritional plants for populations worldwide. Wheat plants are essential in global food security in all countries. Herein, we investigate biochemical responses to salinity stress of selected wheat genotypes to identify the most contrasting salt-responsive genotypes and the mechanisms associated with their differential responses. Ten different Egyptian wheat genotypes were cultivated using soil system and treated for 70 days with diluted seawater (6000 ppm). Salt treatment induced a decrease in plant growth, this reduction showed variation, depending on response of genotypes and plant organs. Two genotypes (G8 and G10) exhibited low level of Na+ accumulation, high K+, Mg2+ and Ca2+, and showed high chlorophyll concentration leading to high net photosynthesis, at salt stress as compared to the other genotypes. Also, they exhibited low level of lipid peroxidation, high total phenolics, total sugars and high proline concentration. These results enhanced reactive oxygen species (ROS) defense and osmotic adjustment. The obtained results confirmed variation in genotypes response to salinity stress, while both G8 and G10 response showed superiority when compared with the other studied genotypes and indicated that the physiological and biochemical traits could be used as screening criteria for selecting salt tolerant genotype.