Orally administeredLacticaseibacillus rhamnosusCRL1505 enhances respiratory immunity, providing protection against respiratory viruses andStreptococcus pneumoniae. However, the capacity of the CRL1505 strain to improve respiratory immunity against Gram-negative bacterial infections has not been evaluated before. The aim of this work was to evaluate whether theLcb. rhamnosusCRL1505 was able to beneficially regulate the respiratory innate immune response and enhance the resistance to hypermucoviscous KPC-2-producingKlebsiella pneumoniaeof the sequence type 25 (ST25). BALB/c mice were treated with the CRL1505 strain via the oral route and then nasally challenged withK. pneumoniaeST25 strains LABACER 01 or LABACER 27. Bacterial cell counts, lung injuries and the respiratory and systemic innate immune responses were evaluated after the bacterial infection. The results showed thatK. pneumoniaeST25 strains increased the levels of TNF-α, IL-1β, IL-6, IFN-γ, IL-17, KC and MPC-1 in the respiratory tract and blood, as well as the numbers of BAL neutrophils and macrophages. Mice treated withLcb. rhamnosusCRL1505 had significantly lowerK. pneumoniaecounts in their lungs, as well as reduced levels of inflammatory cells, cytokines and chemokines in the respiratory tract and blood when compared to infected controls. Furthermore, higher levels of the regulatory cytokines IL-10 and IL-27 were found in the respiratory tract and blood of CRL1505-treated mice than controls. These results suggest that the ability ofLcb. rhamnosusCRL1505 to help with the control of detrimental inflammation in lungs duringK. pneumoniaeinfection would be a key feature to improve the resistance to this pathogen. Although further mechanistic studies are necessary,Lcb. rhamnosusCRL1505 can be proposed as a candidate to improve patients’ protection against hypermucoviscous KPC-2-producing strains belonging to the ST25, which is endemic in the hospitals of our region.