OBJECTIVES: Comprehensive data on the genomic epidemiology of hospital-associated Klebsiella pneumoniae in Ghana are scarce. This study investigated the genomic diversity, antimicrobial resistance patterns, and clonal relationships of 103 clinical K. pneumoniae isolates from five tertiary hospitals in Southern Ghana-predominantly from paediatric patients aged under 5 years (67/103; 65%), with the majority collected from urine (32/103; 31%) and blood (25/103; 24%) cultures. METHODS: We generated hybrid Nanopore-Illumina assemblies and employed Pathogenwatch for genotyping via Kaptive [capsular (K) locus and lipopolysaccharide (O) antigens] and Kleborate (antimicrobial resistance and hypervirulence) and determined clonal relationships using core-genome MLST (cgMLST). RESULTS: Of 44 distinct STs detected, ST133 was the most common, comprising 23% of isolates (n = 23/103). KL116 (28/103; 27%) and O1 (66/103; 64%) were the most prevalent K-locus and O-antigen types. Single-linkage clustering highlighted the global spread of MDR clones such as ST15, ST307, ST17, ST11, ST101 and ST48, with minimal allele differences (1-5) from publicly available genomes worldwide. Conversely, 17 isolates constituted novel clonal groups and lacked close relatives among publicly available genomes, displaying unique genetic diversity within our study population. A significant proportion of isolates (88/103; 85%) carried resistance genes for ≥3 antibiotic classes, with the blaCTX-M-15 gene present in 78% (n = 80/103). Carbapenem resistance, predominantly due to blaOXA-181 and blaNDM-1 genes, was found in 10% (n = 10/103) of the isolates. CONCLUSIONS: Our findings reveal a complex genomic landscape of K. pneumoniae in Southern Ghana, underscoring the critical need for ongoing genomic surveillance to manage the substantial burden of antimicrobial resistance.