Vibrio parahaemolyticus is an important halophilous pathogen that can cause not only a broad range of disease in aquatic animals but also serious seafood-borne illness in humans as a result of the consumption of seafood. To avoid the use of antibiotics, it is critical to identify protective antigens for developing highly effective vaccines against this pathogen. Outer membrane proteins (OMPs) have been suggested as potential vaccine candidates for conferring protection against infection. In this study, we identified novel immunogenic OMPs using an immune assay with serum antibodies from mice infected by V. parahaemolyticus combined with mass spectrometry analysis. Nine OMPs were identified to be immunogenic proteins, and four of these identified proteins with relatively low abundance in OMP profiles, LptD, VP0802, VP1243 and VP0966, were determined to have immunogenicity for the first time. One OMP of interest, VP0802, is highly conserved among major Vibrio species and was proposed to adopt a β-barrel conformation and to be a member of the OprD protein family by bioinformatic analysis. The immunogenicity and protective efficacy of VP0802 were further evaluated by bacterial challenge postimmunization in a mouse model. VP0802 was confirmed to be highly immunogenic and to offer strong protection against V. parahaemolyticus infection, with an RPS of at least 66.7. Efficient clearance of bacteria from the blood of vaccinated mice was also observed. Moreover, upregulation of VP0802 expression was found after bacteria were exposed to fresh sera. These data, taken together, suggest that VP0802 is a promising candidate for the development of a subunit vaccine to prevent V. parahaemolyticus infection.