The study conducted at the Experimental private farm in reclaimed sandy soils in the western district of, El- Minia Governorate, Egypt during winter of two successive seasons of 2020/2021, 2021/2022. To investigate the influences of different irrigation regimes, bio-stimulants and their interaction on lettuce growth, yield and chemical composition, A split-plot design was used, the main plot was irrigation treatments (100% of crop evapotranspiration, 80% ETc and 60% ETc), while the bio-stimulants (control, potassium humate (K-H), biofertilizers (EM) and mixture from K-H plus EM) were assigned in sub-plot. The results showed that in most aspects there was a significant affect between 100% or 80% ETc compared to 60% ETc but insignificant between 100% ETc and 80% ETc in both seasons. Moreover, soil application of the bio-stimulants reduced the negative impact of water deficit compared to control. Combined K-H and EM caused significant increase in all estimated parameters for plant growth and yield. In addition, increase mineral contents, protein and carbohydrate contents in lettuce leaves. In opposite, it causing significant decrease by (30.21, 23.19 and 22.22, 16.73%) for nitrate and prolin through both seasons respectively, compared with control. Furthermore, the highest irrigation water use efficiency was recorded With decreasing the required amount of water (60% ETc). Integration both bio-stimulants caused significant increase in irrigation water use efficiency by 58.65 %in the first season and were 59.14% in the second season. Available N, P and K in soil significantly increase with application of mixture of bio-stimulants followed by sole application of K-H.