Abstract: Enhancing crop tolerance to multiple abiotic stresses is critical for achieving sustainable agriculture. Targeted seed-stage interventions using natural signaling compounds (e.g., melatonin) provide a unique opportunity to establish early stress tolerance that can persist through the critical seed-to-seedling transition. Melatonin seed priming (MSP) is rapidly emerging as a green and climate-smart strategy for enhancing plant stress tolerance. MSP triggers defensive molecular, biochemical, and physiological reprogramming during germination, thereby improving plant performance under subsequent stress conditions. This review synthesizes recent mechanistic insights into how MSP confers stress tolerance across diverse species by modulating redox signaling, hormonal homeostasis, and stress-related gene networks. We elucidate the synergistic potential of MSP when combined with nanoformulations, other priming agents, or beneficial microbes. We also discuss its crosstalk with key signaling pathways to better understand the tolerance mechanisms. Furthermore, we propose a forward-looking strategy that integrates omics, genome editing, speed breeding, and molecular phenotyping methods to improve MSP applications for the development of stress-smart crops. Despite its potential, MSP still faces multiple challenges, including species-specific responses, dosage variability, limited post-priming seed storage stability, and a lack of field-scale validation. Addressing these bottlenecks through high-throughput screening, epigenetic memory assessment, and optimized delivery systems will be essential to fully harness the practical potential of MSP as a sustainable and green approach for future agriculture.