Salicylic acid (SA) and melatonin (MEL) are affordable and effective phytohormones that help mitigate environmental stress. However, the combined benefits of SA and MEL in managing salt and drought stress in lettuce have not been evaluated. Therefore, this study was designed to evaluate the effectiveness of foliar spraying with 1.0 mM SA and 100 µM MEL, either alone or in combination, to enhance lettuce yield, growth, photosynthetic pigments, mineral status, quality, and antioxidant response under four different irrigation regimes. The irrigation practices used were: full irrigation (FI, irrigated with 0.18 dS m−1 at 100 % field capacity [FC]), deficit irrigation (DI, irrigated with 0.18 dS m−1 at 75 % FC), saline irrigation (SW, irrigated with 2.5 dS m−1 at 100 % FC), and deficit saline irrigation (DSW, irrigated with 2.5 dS m−1 at 75 % FC). Additionally, a control treatment (CK) was carried out with foliar application of distilled water and irrigation at 0.18 dS m−1. Compared to the CK, the application of SA, MEL, and SA+MEL increased evapotranspiration by 4.3 %, 8.6 %, and 15.1 %, and yield by 10.2 %, 16.4 %, and 23.8 %, respectively, under FI conditions. Furthermore, the joint application of SA and MEL at FI showed 25.3 % and 20.2 % higher K+/Na+ and Ca2+/Na+ ratios, respectively, compared to the CK. Additionally, the co-application of SA+MEL improved chlorophyll a, b, and carotenoid levels by 19.2 %, 17.2 %, and 20.4 %, respectively, under FI conditions, compared to the CK. Exogenous application of SA, MEL, and SA+MEL also improved total soluble solids by 17.3 %, 18.5 %, and 11.1 % and reduced nitrate content by 9.7 %, 10.4 %, and 13.5 % in lettuce under FI conditions, compared to the CK. The application of SA+MEL together resulted in a more pronounced increase in vitamin C content compared to supplying SA and MEL individually. Moreover, under DSW conditions, exogenous application of SA, MEL, and SA+MEL decreased the membrane stability index by 13.7 %, 9.4 %, and 6.3 %, increased malondialdehyde by 65.4 %, 40.8 %, and 36.6 %, and increased proline content by 68.4 %, 65.4 %, and 96.4 %, respectively, compared to the CK. Moreover, exogenous SA+MEL significantly increased the activities of superoxide dismutase, catalase, peroxidase enzymes under both SW and DSW conditions compared to the SA or MEL. Conversely, the activity of ascorbate peroxidase enzyme showed a gradual decrease in DI, SW, and DSW conditions, relative to the FI conditions. In conclusion, the integrated application of SA+MEL is an optimal strategy to enhance yield, morpho-physiological traits, nutrient homeostasis, antioxidant capacity, and quality in lettuce and mitigate the adverse effects of drought, salinity, and drought-salinity stress.