Abstract: Aquaculture is currently the fastest-growing food supply industry worldwide. Disease control has always been a core concern in the sector of aquaculture. In recent years, the frequency of aquaculture disease outbreaks has increased dramatically due to the continuously increased antibiotic resistance of pathogens. Therefore, it is imperative to find effective antibiotic alternatives for disease control in aquaculture. Bactericidal permeability increasing/lipopolysaccharide binding proteins (BPI/LBPs) are endogenous peptides ubiquitously expressed in aquatic animals that exhibit antimicrobial effects similar to antibiotics. This review presents an overview of current research on BPI/LBPs derived from aquatic animals, the predicted antimicrobial mechanisms of aquatic BPI/LBPs, and the application potential and prospects of aquatic BPI/LBPs as an antimicrobial peptide (AMP) resource. To sum up, the systematic research on aquatic BPI/LBPs may not only enrich AMP resources but also provide new clues for the development of eco-friendly disease control strategies in aquaculture.