The primary objective of this study was to assess the efficacy of the formalized killed vaccine of Vibrio vulnificus on European Eels (Anguilla anguilla) using the immersion method. The experimental fish were subdivided into four groups G1– G4 (30 fish/ group). G1 served as the control and was immersed in saline with 3% NaCl. G2 and G3 were vaccinated by immersion in the formalized killed vaccine for 1h. Fish of G3 (vaccinated) and G4 (non-vaccinated) were experimentally infected with V. vulnificus via immersion in bacterial suspension for 1h. The levels of antibodies in the skin mucus were quantified using the enzyme-linked immunosorbent assay (ELISA) after 7, 14, 21, and 28 days of vaccination. The study results indicated that the vaccinated group (G2) exhibited significantly higher levels of antibodies when compared to the first group and the vaccinated challenge group (G3). The relative percent survival (RPS) was estimated to be 83.38 and 70.88% for G2 and G3, respectively. However, the mortality rate was 80% in G4 infected with the V. vulnificus strain. Moreover, the expression of cytokines IL-1β and TNF alpha immune-related genes in the anterior kidneys of all groups increased in the vaccinated groups (G2 and G3) compared to the control group (G1). Additionally, in the renal parenchyma of G2, G3 and G4 groups, there were markedly active melanoma-macrophage centers observed as pathological changes.