Background <p>The increasing occurrence of multidrug-resistant <i>Klebsiella pneumoniae</i> has emerged as a global health challenge. This study assessed the resistance profiles of clinical <i>K. pneumoniae</i> isolates collected from clinical samples in four hospitals in Osun State, Nigeria.</p> Methods and results <p>A total of 350 clinical samples (urine, pus, sputum, blood, wound swab, and biopsy) were aseptically collected from four hospitals in Osun State, Nigeria. Bacteria were isolated from the collected samples using MacConkey agar, and tentavely characterized as <i>K. pneumoniae</i> using conventional biochemical tests and further confirmed using 16SrRNA <i>K. pneumoniae</i>-species-specific primers. The antibiotic susceptibility pattern was determined using the Kirby-Bauer disc method. In addition, genes encoding carbapenem resistance, outer membrane protein loss genes, and efflux pump genes in the identified <i>K. pneumoniae</i> were also assayed using the Polymerase Chain reaction (PCR) technique. A total of 205 (80%) from 257 isolated bacterial, were identified and genotypically confirmed as <i>K. pneumoniae</i>, out of which 46.34% (<i>n</i> = 95) were resistant to carbapenems. Furthermore, 46.31%, 14.74%,1.05%,76.84%, 73.68%, 91.58%, 61.05%, and 24.21% of the identified <i>K. pneumoniae</i> harbored the genes; VIM-1, NDM-1, IMP, OMPK35, OMKP36, AcrAB, TolC, and MdtK, which codes for carbapenemase, outer membrane porin loss and efflux pump genes respectively.</p> Conclusions <p>Taken together, this present study indicated that the resistance of <i>K. pneumoniae</i> to carbapenems is seemingly higher and co-existing of carbapenem resistant genes compared with previous studies in Osun State, resulting to challenge in infection treatment. Therefore, it is of utmost importance to sensitize the public against indiscriminate and/or misuse of antibiotics.</p>