Drought stress poses a significant threat to wheat production worldwide by impairing physiological and biochemical processes, necessitating innovative approaches to enhance crop resilience. This study explores the role of L-cysteine desulfhydrase (L-DES), a key enzyme involved in hydrogen sulfide (H2S) production, in mediating melatonin-induced drought tolerance in bread wheat (Triticum aestivum L.). Wheat plants were treated with 0.10 mM melatonin prior to drought induction, with water availability maintained at 80% (well-watered) or 40% (drought-stressed) of field capacity. Drought stress led to a significant decline in plant biomass, photosynthetic efficiency (Fv/Fm), chlorophyll content, and relative water content, while simultaneously increasing oxidative stress markers including hydrogen peroxide (H2O2), malondialdehyde (MDA), and electrolyte leakage, indicating severe cellular damage. Melatonin application mitigated drought-induced oxidative damage by enhancing antioxidant defense mechanisms, scavenging reactive oxygen species (ROS), and reducing lipid peroxidation. It also maintained photosynthetic efficiency by preserving chlorophyll content and stabilizing photosystem II activity. Additionally, melatonin upregulated glyoxalase system enzymes (Gly I and Gly II) to detoxify methylglyoxal and increased L-DES activity and endogenous hydrogen sulfide (H2S) levels, thereby improving osmotic balance and stress tolerance. The critical role of L-DES was confirmed using DL-propargylglycine (PAG), an L-DES inhibitor, which significantly suppressed melatonin's protective effects. However, co-treatment with sodium hydrosulfide (NaHS), an H2S donor, reversed PAG's inhibition, highlighting the indispensable role of L-DES and H2S in enhancing melatonin-induced drought resilience. This study establishes melatonin as a promising bio-stimulant for sustainable wheat production in arid regions and elucidates the interplay between L-DES activity and H2S signaling in enhancing drought tolerance mechanisms.