The bactericidal permeability-increasing protein (BPI) and lipopolysaccharide binding protein (LBP) are fundamental to innate immunity. However, their functional diversity and evolutionary conservation in ecologically crucial invertebrates, such as oysters, remain largely understudied. In this study, we identify and characterize a novel homolog of BPI/LBP, designated as ChBPI/LBP in the Hong Kong oyster (Crassostrea hongkongensis). Through structural and phylogenetic analysis, we identify ChBPI/LBP as a distinct member of the BPI protein family, with a high isoelectric point (pI of 9.26), indicating potent cationic BPI-like bactericidal function. We found that ChBPI/LBP is constitutively highly expressed at mucosal sites such as the gills and is rapidly upregulated in hemocytes following a challenge with Aeromonas hydrophila. Recombinant ChBPI/LBP demonstrated potent and specific bactericidal activity against Gram-negative pathogens. These findings suggest that ChBPI/LBP is an important antimicrobial peptide (AMP) effector in the oyster’s immune response. This work provides novel perspectives on the evolutionary mechanisms of innate immunity in bivalves and may have implications for disease management in aquaculture.