Helicobacter pylori infects the gastric mucosa and induces chronic gastritis, peptic ulcers, and gastric cancer. Research has demonstrated that vaccination can induce a protective immune response and prevent H. pylori infection. Oral administration of the Lactococcus lactis live-carrier vaccine is safe and easily complied with by the public. In this study, two recombinant L. lactis strains were constructed that expressed antigens of H. pylori urease subunit alpha (UreA) and UreA fused with Escherichia coli heat-labile toxin B subunit (LTB-UreA), named LL-UreA and LL-LTB-UreA, respectively. The expression of antigen proteins was confirmed by Western blotting analysis. Survival assessment indicated that the engineered L. lactis could colonize in the digestive tract of BALB/c mice up to 10 days after the last oral administration with our immunization protocol. The ability to induce immune response and immune protective efficacy of the L. lactis were confirmed. These results indicated that oral administration with LL-UreA or LL-LTB-UreA could induce UreA-specific mucosal secretory IgA (sIgA) and cellular immune response, significantly increasing the cytokines levels of interferon-gamma (IFN-γ), interleukin (IL)-17A, and IL-10, together with the proportion of CD4+IFN-γ+ T cells and CD4+IL17A+ T cells. More importantly, oral administration of LL-UreA and LL-LTB-UreA brought about effective protection in mice to prevent H. pylori infection, especially LL-UreA, resulting in 70% of mice showing no H. pylori colonization and the remaining 30% showing only low levels of colonization. These findings underscore the potential of using orally administered engineered L. lactis vaccines to prevent H. pylori infection.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.