Swine are often asymptomatic carriers of Salmonella spp., a leading cause of human bacterial foodborne disease. Vaccination against Salmonella is effective for protecting animal health and enhancing food safety. However, with >2500 Salmonella serovars, current vaccines for swine offer limited cross-protection against heterologous serovars. Also, existing vaccines can interfere with surveillance programs that monitor the Salmonella status of swine herds. To overcome Salmonella vaccine limitations, we rationally designed and constructed an attenuated Salmonella enterica serovar Typhimurium vaccine (BBS 866) by deleting multiple small regulatory RNA (sRNA) genes (omrA, omrB, rybB, micA, and invR) in combination with an rfaH mutation. We vaccinated swine intranasally at 3-weeks of age with PBS (mock-vaccinated), BBS 866 or BBS 202 (S. Typhimurium rfaH, Bearson et al., Front Vet Sci 2014;1:9.) and challenged at 7-weeks of age with virulent S. Choleraesuis, a swine pathogen. Vaccination with BBS 866 enhanced protection against S. Choleraesuis by significantly limiting the duration of fever, weight loss, the levels of circulating INFγ, and the total number of swine with S. Choleraesuis septicemia. Vaccination with either BBS 866 or BBS 202 significantly reduced S. Choleraesuis colonization of both systemic (spleen and liver) and gastrointestinal (Peyer's Patch, Ileocecal lymph nodes, and cecum) tissues. Similar to our earlier report for BBS 202, the BBS 866 vaccine strain can be used in swine without compromising the differentiation of infected from vaccinated animals (DIVA). Therefore, the attenuated S. Typhimurium BBS 866 strain, containing mutations in rfaH and multiple sRNAs, addresses the limitations of current Salmonella vaccines by providing cross-protection against Salmonella serovars in swine without interfering with established monitoring programs for Salmonella surveillance.