Drought adversely affects crop production in areas with water shortages. In such areas, various methods need to be implemented to alleviate the effect of water stress on plants. Nitric oxide (NO) is an important plant growth regulator that affects various physiological processes. In this study, we determined ways to increase water-stress tolerance of lettuce by applying exogenous sodium nitroprusside (SNP, a donor of NO). In total, 12 treatments were administered, including three SNP doses (0, 50, and 100 µM) and four levels of irrigation (I100, I80, I60, and I40). An increase in the doses of NO partially increased the water consumption of lettuce under full and deficit irrigation conditions. The highest water consumption (125.1 mm) and the highest yield (39.1 t/ha) were recorded for lettuce plants that were administered the I100 treatment with 100 µM SNP. SNP significantly increased the lettuce yield and irrigation water productivity (IWP) under deficit irrigation and full irrigation. SNP promoted chlorophyll synthesis by increasing photosynthesis. The application of 100 µM SNP increased catalase (CAT) activity approximately three times compared to CAT activity in the control group, and it also significantly increased peroxidase (POD) activity. Additionally, high doses of SNP reduced membrane damage in lettuce leaves. These results indicated that under water stress, exogenous NO improves photosynthesis by increasing chlorophyll synthesis, activates antioxidant enzymes, such as CAT and POD, protects lettuce against oxidative damage, and increases irrigation water productivity, thus increasing the yield.