Klebsiella pneumoniae is a significant Gram-negative pathogen, responsible for severe urinary tract infections, bloodstream infections, and pneumonia, and poses a substantial public health threat due to its antibiotic resistance. To explore its molecular characteristics, 288 clinical isolates were collected from a Sicilian transplantation hospital between 2008 and 2017, chosen for their carbapenem resistance. Genome sequencing was conducted to analyze their molecular profile, including resistance and virulence genes. This genetic data, along with sequences from 179 patients in a Tuscan hospital, was utilized in reverse vaccinology to identify potential klebsiellal antigens. Seven antigens, four of which were prevalent in most Italian carbapenem-resistant K. pneumoniae clinical isolates, were identified. Bioinformatics tools confirmed the antigenic potential of these proteins and allowed for the identification of T and B cell epitopes, facilitating the rational design of a multiepitope vaccine against carbapenem-resistant K. pneumoniae strains. The vaccine candidate underwent thorough analysis by bioinformatics tools to assess its antigenicity, solubility, allergenicity, toxicity, physical and chemical parameters, and secondary and tertiary structures. Molecular docking binding energies to TLR-2 and TLR-4, essential innate immunity receptors in the immune response against K. pneumoniae infections, along with molecular dynamics simulations of these complexes, supported active interactions. A codon-optimized multiepitope sequence cloning strategy was proposed for recombinant vaccine production in classical bacterial vectors. Finally, a 3-dose immunization simulation with the multiepitope construct induced both cellular and humoral immune responses, suggesting its potential as a vaccination strategy against carbapenem-resistant K. pneumoniae and warranting further validation.