To resolve the ubiquitous crisis of antibiotic resistance rose due to overuse/misuse of certain drugs and antibiotics against which pathogenic bacteria have developed resistance; there is a need to replace these antibiotics with next-generation antibiotics and Zoo therapy is one of the important measures to attain this goal. In the context of reducing antibiotic resistance, fish epidermal mucus has been proven to be a boon to overcome this alarming issue. It holds valuable antimicrobial components in the form of antimicrobial peptides, glycoproteins, and antimicrobial bacteria which assist fishes to guard themselves against pathogens in the aquatic ecosystem. This study emphasizes the composition and role of fish skin mucus in disease resistance and describes the significance of antipathogenic bacteria isolated from skin mucus in protecting fish from various infections thus suggesting the means to replace antibiotics with next-generation drugs obtained from fish skin mucus taking a step towards sustainability of the ecosystem.