<p>Skin ulcerative disease (SUD) in sea cucumbers poses a significant threat to marine biodiversity, aquaculture sustainability, and ecosystem health. Characterized by localized lesions that can progress to extensive tissue necrosis, SUD arises from complex interactions involving microbial infections, environmental stressors, and impaired host immunity. Advances in omics technologies have greatly advanced our understanding of SUD pathogenesis. Genomics has revealed genetic determinants of susceptibility, resistance, and host pathogen interactions, while transcriptomics has provided insights into dynamic gene expression changes in immune signaling and stress response pathways. Proteomics has identified protein networks involved in inflammation, tissue remodeling, and antioxidant defenses, whereas metabolomics has uncovered metabolic shifts linked to oxidative stress, lipid remodeling, and energy imbalance. The integration of these approaches has highlighted potential biomarkers, predictive signatures, and therapeutic targets, with promising interventions such as bacteriophage therapy and IgY-based treatments. This review synthesizes current omics-driven insights and underscores the importance of multi-omics integration for advancing effective disease management strategies and enhancing aquaculture resilience.</p>