Multidrug-resistant Edwardsiella tarda has been reported as the main causative agent for massive fish mortality. The pathogen is well-known for causing hemorrhagic septicemia in fish and has been linked to gastrointestinal infections in humans. Formalin-inactivated Edwardsiella vaccination has previously been found to be ineffective in aquaculture species. Therefore, based on E. tarda’s integrated core complete sequenced genomes, the study aimed to design a subunit vaccine based on T and B cell epitopes employing immunoinformatics approach. Initially, the top immunodominant and antigenic epitopes were predicted from the core complete sequenced genomes of the E. tarda genome and designed the vaccine by using linkers and adjuvant. In addition, vaccine 3D structure was predicted followed by refinement, and molecular docking was performed for the analysis of interacting residues between vaccines with TLR5, MHC-I, and MHC-II, respectively. The final vaccine constructs demonstrated strong hydrogen bond interactions. Molecular dynamic simulation of vaccine-TLR5 receptor complex showed a stable structural binding and compactness. Furthermore, E. coli used as a model organism for codon optimization proved optimal GC content and CAI value, which were subsequently cloned in vector pET2+ (a). Overall, the findings of the study imply that the designed epitope vaccine might be a good option for prophylaxis for E. tarda.