Objective To analyze the molecular epidemiology and genomic evolutionary relationship of clinically isolated ST15 carbapenem-resistant Klebsiella pneumoniae (CRKP) in Wuxi City of Jiangsu Province, and provide scientific basis for formulating regional precise prevention and control strategies. Methods Eighteen clinically isolated non-repetitive ST15-CRKP strains from a tertiary first-class hospital in Wuxi City from January 2021 to December 2024 were collected. Bacterial strains were identified and underwent antimicrobial susceptibility testing. Whole genome next-generation sequencing via Illumina NovaSeq X Plus platform was performed on all strains. Based on the results, 2 highly virulent strains were screened and analyzed by the Oxford Nanopore PromethION platform to obtain high-quality complete genome maps. Resistance genes, virulence genes, plasmid carrying status, and genomic structural characteristics of the strains were analyzed, and the phylogenetic tree was constructed based on single nucleotide polymorphisms (SNPs). Virulence of selected strains was evaluated by Galleria mellonella infection model. Results Antimicrobial susceptibility testing results showed that all strains were generally resistant to broad-spectrum antimicrobial agents such as carbapenems, but sensitive to tigecycline and polymyxin. Among the 18 infected patients, 77.8% were aged≥60 years old, and 77.8% were male. The major specimens were respiratory specimens (accounting for 44.4%, including 7 sputum specimens and 1 bronchoalveolar lavage fluid) and blood specimens (33.3%, n=6), the rest were from bile, urine, and ducts. Genomic evolutionary analysis showed that the strains could be divided into two clone groups, KL19-O1 and KL112-O1, carrying carbapenemase genes such as bla_KPC-2, bla_NDM-5, and bla_OXA-232. Among them, 4 strains were hypervirulent and resistant to carba-penems, exhibiting a unique rmpA2⁺/iutA⁺/rmpA^- virulence gene profile. Galleria mellonella infection model confirmed that the virulence was higher than non-hypervirulent strains (P=0.015). Plasmid analysis showed that bla_KPC-2 was located within the IS26-Tn4401b-IS26 complex transposon structure of the IncFII_K type plasmid, bla_OXA-232 was located in the ColKP3 type plasmid, and the virulence gene was carried by the IncHI1B (pNDM MAR)/IncFIB_K37 fusion plasmid. Conclusion ST15-CRKP in Wuxi area is dominated by KL19-O1-bla_KPC-2 clone epidemic, but hypervirulent subclones carrying rmpA2⁺/iutA⁺/rmpA^- and belonging to KL112-01 have emerged. Continuous monitoring on the genomic evolution of ST15-CRKP is crucial for guiding clinical medication as well as developing regional precision prevention and control strategies.