Lumpfish (Cyclopterus lumpus) has become the predominant cleaner fish species used in North American salmon aquaculture for sea lice (e.g., Lepeophtheirus salmonis) biocontrol. Lumpfish utilization has contributed significantly towards eliminating the utilization of chemotherapeutants by effectively controlling the abundance of this damaging pest of Atlantic salmon (Salmo salar) aquaculture. Vibrio anguillarum is a frequent pathogen of lumpfish in Atlantic Canada. Here, several vaccine trials against V. anguillarum were conducted. We determined that the V. anguillarum growth conditions are essential for expressing protective antigens in the vaccine formulation. Generic commercial vaccines provide between 2-55% protection against V. anguillarum, which does not adequately protect the lumpfish. Generic or autogenous vaccines delivered by mucosal routes (e.g., dip or bath) stimulates the naïve fish. However, only systemic immunization regimes (e.g., intraperitoneal injection) induced significant protective immunity against the lethal V. anguillarum systemic or mucosal challenge. Mucosal immunization conferred an evident immune stimulation, but not immune protection. A combination of dip immune stimulation and intraperitoneal boost immunization may confer a longer-lasting immune protection, which could be optimal for lumpfish health management, and important to the continued success of cleaner fish biocontrol in salmon aquaculture.