ABSTRACT Waterlogging is a major abiotic stress that severely impedes sesame growth and productivity. Melatonin has emerged as a multifaceted regulator in plant stress responses, but its protective mechanisms against waterlogging in sesame, particularly at the proteomic level, remain largely unexplored. A pot experiment was conducted using two sesame genotypes with contrasting waterlogging tolerance (sensitive JHM and tolerant PYH) under well‐drained, waterlogging, and waterlogging with melatonin pretreatment conditions. Results showed that waterlogging significantly inhibited plant growth, impaired root architecture, and induced oxidative stress, with more severe impacts on sensitive genotype JHM. Exogenous melatonin application markedly mitigated these adverse effects, reducing the decline in plant height and root growth parameters. Melatonin balanced osmotic pressure by modulating proline and soluble protein content, alleviated oxidative damage by decreasing MDA and H₂O₂ accumulation, and enhanced the activities of SOD, POD, and CAT. It also ameliorated stress signaling by downregulating the accumulation of ABA and ACC, while elevating endogenous melatonin levels. The PYH possessed a superior constitutive antioxidant capacity and hormonal stability, while melatonin was particularly beneficial for JHM. Proteomic analysis identified 1846 differentially expressed proteins (DEPs) in roots of JHM between waterlogged and melatonin‐treated plants. These DEPs were predominantly enriched in metabolic pathways, phenylpropanoid biosynthesis, glutathione metabolism, and ROS metabolic processes. MT priming upregulated the expression of superoxide dismutase peroxidase 7, and peroxidase 15‐like while downregulated hydrogen peroxide induced protein 1, which were consistent with the results of physiological analysis in JMH. Protein‐protein interaction analysis highlighted key proteins like RPL6 and RPL4 as potential hubs within the melatonin‐mediated ROS metabolic network. This study provides a comprehensive physiological and molecular elucidation of the multifaceted mechanisms by which melatonin confers waterlogging tolerance, establishing a theoretical foundation for its application in waterlogged regions.