Abstract Inflammation is a highly regulated process triggered by the presence of pathogens, injury or trauma. Specialized proresolving mediators (SPMs) are endogenous lipid-derived molecules, which regulate the resolution of inflammation. Resolving inflammation is critical for maintaining homeostasis while assuring immune protection against pathogens, such as influenza virus. We previously showed that the SPM 17-hydroxydosahexaenoic acid (17-HDHA) increased human B cell antibody production in vitro and promoted differentiation towards an antibody-secreting phenotype. Herein, we used a pre-clinical influenza virus immunization mouse model to study the effects of 17-HDHA in vivo. Mice immunized with influenza-derived hemagglutinin (HA) protein plus 17-HDHA have enhanced HA-specific IgM and IgG production compared to mice immunized with HA alone. Enhanced HA-specific antibody production was due to plasma cell increase in the bone marrow. HA-specific antibodies were protective against live influenza viral infection as they decreased morbidity and mortality following viral challenge. Our study shows that DHA-derived SPMs play an important role in enhancing B cell-mediated immunity. An enhanced antigen-specific immune response promotes faster pathogen clearance, and thus return to homeostasis. In addition, these new findings highlight the potential applications of SPMs as new endogenous and non-toxic adjuvants or vaccine “boosters”.