Drought stress is one of the major environmental stresses limiting global agricultural productivity. It negatively affects plant growth and development, reducing yields and causing substantial economic losses. Plants have evolved complex mechanisms involving signaling molecules, ROS, and regulatory pathways to cope with drought-induced stress. Notably, melatonin, a bioactive compound, has been identified as an important mediator of plant responses to stress. Melatonin regulates the signaling of reactive species, controls osmotic balance, and reinforces antioxidant defense systems, increasing drought tolerance. In the present study, we delve into the complex interaction between melatonin and ROS signaling in mitigating drought stress in plants. We highlight how melatonin modulates ROS signaling and enhances plant tolerance by activating stress-inducible genes, modulating antioxidative enzymes, and regulating water homeostasis. Moreover, this chapter covers current research on the synergistic effects of melatonin and ROS, leading plants to acclimate to drought stress. Finally, we also discuss the potential role of melatonin-based strategies as novel tools in crop improvement approaches to mitigate the effects of drought stress on future crop improvement practices in drought-prone regions to promote agricultural sustainability.