<p>Cotton (<i>Gossypium</i> species), a globally vital crop for fiber and oil, faces severe production challenges due to drought stress. However, cotton's key adaptation lies in the&#xa0;precise regulation of stomatal movement under drought stress, yet the mechanisms linking its reactive oxygen species (ROS) signaling, hormonal pathways, and stomatal dynamics remain insufficiently elucidated. This review synthesizes current knowledge on drought responses in cotton and evaluates the advanced strategies, including multi-omics, nanobiotechnology, and computational modelling through the&#xa0;OnGuard platform for enhancing drought resilience. We highlighted the central role of abscisic acid (ABA) and jasmonic acid (JA) in coordinating stress signaling in cotton, involving calcium ions (Ca²⁺) as key mediators. The accumulation of osmolytes and modulation of antioxidant defenses are found&#xa0;to be critical for maintaining cellular functions. Furthermore, we deciphered the molecular underpinnings governed by transcription factors (<i>WRKY</i>, <i>MYB</i>, and <i>ABF2</i>) regulated through ABA-mediated pathways that orchestrate the&#xa0;expression&#xa0;of&#xa0;cotton defense genes. Therefore, we emphasized that decoding the integrated mechanisms of stomatal regulation and ROS balance could provide a strategic pathway for developing high-yielding and drought-resilient cotton genotypes. Thus, integrating the ABA-mediated stomatal kinetics, ROS homeostasis, and transcription factor networks could pave a promising framework for developing drought-resilient cotton genotypes.</p> Graphical Abstract <p></p>