Water scarcity in Egypt presents significant challenges to agriculture, necessitating the development of innovative strategies to enhance vegetable crops resilience and productivity under limited water conditions. This study investigates the effects of organic fertilization and melatonin application on the performance of crisphead lettuce (Lactuca sativa L.) under water stress conditions. The experiment was conducted over two growing seasons (2022 and 2023) at the research farm of the Faculty of Agriculture, Mansoura University, Egypt and evaluated the impact of three irrigation regimes as a main factor (100%, 80%, and 60% of evapotranspiration, ETO) combined with different organic fertilization treatments as a sub-main factor ( without, plant compost, chicken manure compost and vermicompost) and foliar application of melatonin as a sub-sub main factor (0.0 and 70 mmol L-1). Results indicated that reducing irrigation levels significantly increased enzymatic antioxidant activities, including superoxide dismutase, peroxidase, and catalase. Organic fertilization, particularly with plant compost, improved leaf chemical constituents and photosynthetic pigments, while melatonin application further enhanced these traits. Growth performance metrics, such as fresh and dry weight, leaf area, and relative water content, showed significant improvements with combined treatments of organic fertilizers and melatonin under water-limited conditions. For example, in the first season, the maximum head weight of 1124.38 g was achieved with full irrigation (100% ETO). However, reducing the irrigation level to 80% and 60% resulted in lower head weights of 955.67 g and 653.67 g, respectively. Among the organic fertilization treatments, plant compost produced the highest head weight at 972.56 g, while the control treatment had the lowest at 770.50 g. Additionally, foliar application of melatonin increased the head weight to 931.94 g, compared to 890.53 g in the control treatment. This study highlights the potential of integrated organic and hormonal treatments to mitigate the adverse effects of water stress on lettuce production. Future research should focus on refining these strategies and exploring their applicability to other crops to further address the challenges posed by water scarcity in arid regions like Egypt.