Distribution of selenium (Se) in soils around the world is not identical and many soils are classified as Se-poor soils. Therefore, Se fortification of crops grown on these soils is crucial, where increasing Se intake by human - below toxic threshold - is vital for better health. The recent work aims to investigate the possible use of Se to alleviate the detrimental effects of soil salinity on lettuce and enhance its growth, yield quality and Se enrichment. Field experiments were conducted during two successive seasons (2016 and 2017) in salt-affected soil (EC 4.49 dS m−1, pH 8.65) using four concentrations of Se (0, 50, 75 and 100 ppm) by three different application methods. Antioxidant capacity, ion leakage, Se content in plant and soil, yield and vegetative parameters of lettuce were measured. The results showed that Se addition mitigated the detrimental effect of salinity on lettuce growth and its development. Se application (100 ppm) increased also the head weight, leaf area, leaves dry weight and chlorophyll content by 46.4, 66.4, 61.8 and 31.5%, respectively, compared to control plants. Likewise, catalase (CAT) and ascorbate peroxidase (APX) activities increased by 108.8 and 123.6%, respectively, as a result for using 100 ppm of Se. Otherwise, Se (100 ppm) reduced the electrolyte leakage from lettuce leaves by 68.4% against control. The positive effect of Se (100 ppm) on lettuce under salinity was fully verified with data of total yield which increased by 42.1% over control. Foliar application increased Se content in lettuce without exceeding the toxic level and residual Se in soil was the lowest among other treatments. The present work reports that in salt-affected soils spraying lettuce with Se (100 ppm) improves its growth, antioxidant capacity, Se fortification and yield quality.