A hypervirulent carbapenem-resistant Escherichia coli (CREC) clone, ST410 B5/H24RxC, has emerged globally, causing outbreaks in a Chinese children's hospital. This clone, identified through genomic analysis, is more virulent and resistant than the previously known B4/H24RxC clone. B5/H24RxC lacks the blaOXA-181 gene on an X3 plasmid but carries a F-type plasmid with blaNDM-5. It also contains a high pathogenicity island (HPI) and a novel O-antigen gene cluster, contributing to its increased virulence and resistance. The clone was found in 10 countries between 2015 and 2021, with a significant presence in China. Comparative genomic analysis revealed that B5/H24RxC has more antimicrobial resistance genes and virulence factors than B4/H24RxC. It grows faster in vitro and is more virulent in vivo, as shown in wax moth larvae infection models. The clone's global spread is attributed to recombination and horizontal gene transfer. The study highlights the ongoing evolution of ST410 towards increased resistance and virulence, posing a significant public health threat. The findings emphasize the need for further research to understand the mechanisms driving the emergence and spread of this hypervirulent CREC clone.A hypervirulent carbapenem-resistant Escherichia coli (CREC) clone, ST410 B5/H24RxC, has emerged globally, causing outbreaks in a Chinese children's hospital. This clone, identified through genomic analysis, is more virulent and resistant than the previously known B4/H24RxC clone. B5/H24RxC lacks the blaOXA-181 gene on an X3 plasmid but carries a F-type plasmid with blaNDM-5. It also contains a high pathogenicity island (HPI) and a novel O-antigen gene cluster, contributing to its increased virulence and resistance. The clone was found in 10 countries between 2015 and 2021, with a significant presence in China. Comparative genomic analysis revealed that B5/H24RxC has more antimicrobial resistance genes and virulence factors than B4/H24RxC. It grows faster in vitro and is more virulent in vivo, as shown in wax moth larvae infection models. The clone's global spread is attributed to recombination and horizontal gene transfer. The study highlights the ongoing evolution of ST410 towards increased resistance and virulence, posing a significant public health threat. The findings emphasize the need for further research to understand the mechanisms driving the emergence and spread of this hypervirulent CREC clone.