<p>Drought, high temperature, and salinity are critical abiotic stresses that severely restrict global agricultural yield. With the accelerating pace of climate change, these stresses are projected to become more frequent, severe, and prolonged, thereby posing critical threats to crop production and food security. Plants employ complex molecular networks in response to abiotic challenges, involving diverse genes, proteins, metabolites, and regulatory pathways. Among these, key biomolecules such as flavonoids, melatonin, and abscisic acid (ABA) have emerged as pivotal modulators of stress tolerance. Flavonoids function as potent antioxidants and regulators of stress-signaling cascades; melatonin contributes to osmotic adjustment, antioxidant defense, maintenance of photosynthetic efficiency, and modulation of stress-responsive gene expression; while ABA acts as a central regulator of osmotic and ionic homeostasis, gene regulation, and stomatal dynamics, and has been widely studied under multiple abiotic stresses. Both exogenous application and genetic enhancement of these stress regulators—through priming, analogue treatments, or transgenic approaches—have provided important insights into their synergistic roles in plant stress resilience. Harnessing flavonoids, melatonin, and ABA not only strengthen intrinsic defense mechanisms but also offers novel strategies for crop improvement. This review underscores the critical importance of these regulators in mitigating environmental stress impacts, highlights current advances, and outlines future research priorities aimed at developing climate-resilient crops to safeguard global food and feed security.</p>