is an opportunistic pathogen. Its main virulence factors are exotoxins, which are the etiological agents of enteritis necroticans and enterotoxemia caused in livestock (cattle, sheep, and rabbits). Here, we demonstrated effective immune protection for rabbits against α, β, and ε exotoxins of provided by an oral tetravalent bait probiotic vaccine delivering α, ε, β1, and β2 toxoids of . Results showed that the recombinant probiotic had good segregational stability and good colonization ability in the rabbit intestinal tract. Oral administration of the probiotic vaccine can effectively elicit significant levels of antigen-specific mucosa sIgA and sera IgG antibodies with exotoxin-neutralizing activity. Additionally, oral immunization with the probiotic vaccine effectively promoted lymphoproliferation and Th1/Th2-associated cytokine production. The protection rate of immunized rabbits with the probiotic vaccine was 80% after challenging rabbits with a combination of . (toxinotypes A, C, and D) and exotoxin mixture, which was better than the 60% provided by a commercial inactivated A, C, and D trivalent vaccine. Moreover, obvious histopathological changes were observed in the intestinal tissues of rabbits in the commercial vaccine and PBS groups. The bait probiotic vaccine can provide effective protection against exotoxins, suggesting a promising vaccination strategy.