Yersinia enterocolitica is an important human pathogen. Yersiniosis, caused by Y. enterocolitica, has become more prevalent globally in recent years. Prevention of yersiniosis still remains a challenge, and an efficacious and safe vaccine that confers protection against this enteric pathogen needs to be developed. In this study, a novel vaccine based on the bacterial ghost, in combination with mutation of the Y. enterocolitica msbB gene, was developed and the immunopotency of this vaccine was evaluated in mice. Significant levels of IgG1/IgG2a antibodies and IL-4/IFN-γ cytokines were detected after mice were administered this vaccine intragastrically, indicating that a Th1/Th2-mediated mixed immune response was stimulated. Importantly, mutation of the msbB gene efficiently reduced secretion of the proinflammatory cytokines IL-1β, IL-6 and TNF-α, suggesting a reduction in inflammatory reaction caused by lipopolysaccharide. In addition, when challenged with a dose that was 100-fold the minimal lethal dose of the virulent wild strain of Y. enterocolitica, this mutated ghost vaccine was capable of eliciting the same effective protection (80%) in comparison with the non-mutated ghost strain, and the survival time was extended by at least two days. Together, our results demonstrated that this novel ghost bacterial strain could be used as a safe and effective vaccine against Y. enterocolitica.