Although the individual influences of silicon (Si) and melatonin (MT) have been widely studied under various abiotic stresses, little is known about their interaction under drought stress. In this study, an experiment in pots was carried out to investigate the potential of an individual or combined foliar application of silicon (Si) and melatonin (ML) (control (ck), water spray, 4.0 mM Si, 200 µM ML, and 4.0 mM Si + 200 µM ML) on wheat grown at two different water-holding capacity levels (80% well-water condition and 40% drought stress) in order to check of grain yield and some important physiological characteristics. Under drought stress conditions, grain yield and yield attributes, water content and photosynthetic efficiency of wheat crops were significantly decreased. Application of Si+ ML significantly improved leaf pigments (Chl a, Chl b and Chll a + b), leaf relative water content (RWC), proline, total soluble sugars, and total soluble protein. As well as, the activities of important antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and ascorbate peroxidase (APX) were effectively boosted through the combined application of Si + ML. This improvement was correlated with an obvious decrease in the levels of MDA, H2O2, and electrolyte leakage and increased water use efficiency. Conclusively, the combination of Si + ML significantly enhanced the 20.21% yield and various morpho-physiological attributes of drought-stressed wheat plants and can be recommended as a promising treatment to enhance wheat productivity in drought-affected regions. Additionally, the results of this study may open up a whole new area of research opportunities at the transcriptional level to further understand the mechanisms underlying how Si + ML integrates and interacts with plants under drought stress.