Aims Genotype VII Newcastle disease (ND) is one of the most epidemic and serious infectious diseases in the poultry industry. A novel vaccine targeting VII Newcastle disease virus (NDV) is still proving elusive. Methods and Results In this study, we constructed regulated delayed lysis Salmonella strains expressing either a fusion protein (F) alone under an eukaryotic CMV promoter or together with chicken IL-18 (chIL-18) as a molecular adjuvant under prokaryotic P-trc promoter, named pYL1 and pYL23 respectively. Oral immunization with recombinant strains induced NDV-specific serum IgG antibodies in both pYL1- and pYL23-immunized chickens. The presence of chIL-18 significantly increased lymphocyte proliferation in immunized chickens, as well as the percentages of CD3(+)CD4(+) and CD3(+)CD8(+) T cells in serum, even if a statistically significant difference did not exist. After a virulent challenge, pYL23 immunization provided about 80% protection at day 10 postinfection, compared with 60% of protection offered by pYL1 immunization and 100% protection in the inactivated vaccine group, indicating the enhanced immune response provided by chIL-18, which was also confirmed by histochemical analysis. Conclusions Recombinant lysis Salmonella-vectored DNA vaccine could provide us a novel potential option for controlling NDV infection. Significance and Impact of the Study This study took use of a regulated delayed lysis Salmonella vector for the design of an orally administrated vaccine against NDV.