Melatonin, a well-known indoleamine, has emerged as a critical regulator of plant immunity, modulating various physiological and molecular pathways to mitigate biotic and abiotic stresses. Recent advances in omics technologies have provided unprecedented insights into the intricate roles of melatonin in plant–pathogen interactions. Genomic studies have identified key genes involved in melatonin biosynthesis and signaling, while transcriptomic analyses have elucidated its influence on defense-related gene expression networks. Proteomic approaches have revealed melatonin-induced changes in pathogenesis-related proteins and antioxidant enzymes, which contribute to enhanced disease resistance. Furthermore, metabolomic studies highlight the melatonin-mediated accumulation of secondary metabolites with antimicrobial properties, while epigenomic investigations uncover its role in immune memory through DNA methylation and histone modifications. This chapter integrates multi-omics strategies to decipher the molecular basis of melatonin-induced biotic and abiotic responses, emphasizing its potential applications in sustainable crop management.