The scarcity of clean water resources is increasing the use of salty water with high EC (electrical conductivity) for irrigation, particularly in water-stressed areas. In this study, the responses of lettuce plants grown under water stress to the increased sodium chloride (NaCl) stress were determined. Therefore, an experimental trial with 15 treatments, including five different water salinity levels (from 0.3 dS/m (control) to 6.0 dS/m) and three different irrigation regimes (from full irrigation to 50% water stress), was conducted. Increasing the NaCl concentration in water decreased the evapotranspiration (ET) of lettuce under full and deficit irrigation conditions. The highest fresh weight yield was obtained in plants treated with 1.5 dS/m water salinity under full irrigation conditions, and increasing the water salinity level resulted in a decrease in yield. Lettuce showed greater sensitivity to water stress than to salinity stress, and yield losses were 29.8% at 25% water stress and 64.2% at 50% water stress compared to those under full irrigation. On the other hand, the 1.5 dS/m NaCl level significantly increased the contents of lettuce's color pigments, such as Chl-a and Chl-b, compared to the control and upregulated the non-enzymatic antioxidants of defense systems such as carotenoid and proline and the enzymatic antioxidant of defense systems like catalase (CAT). Leaf sodium content increased significantly (+357%) in plants exposed to high NaCl stress level (6.0 dS/m), compared to the control, while mineral contents such as nitrogen (-20.0%), iron (-49.3%), sulfur (-23.9%), and lead (-19.7%) decreased significantly. Our findings showed that lettuce could be irrigated with saline water with a threshold electrical conductivity of 1.5 dS/m without yield loss, but water with a salinity of more than 4.5 dS/m resulted in significant yield losses.