Carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) represent a significant global threat. The emergence of dual CP-CRE is particularly alarming, as they can potentially compromise the efficacy of newer antibiotics, further decreasing therapeutic alternatives. Herein, we report the emergence of multiple species of CP-CRE recovered from invasive infections in Chile that simultaneously harbor
bla
KPC
and
bla
NDM
and provide an in-depth genomic characterization of these worrisome pathogens. We collected carbapenem-resistant Enterobacterales (CRE) isolates from invasive infections over a 4-year period, across 11 healthcare centers in Chile. Bacterial species and the presence of carbapenemase genes were confirmed using MALDI-TOF and PCR assays, respectively. Antimicrobial susceptibility testing was conducted through disk diffusion and broth microdilution methods. Dual CP-CRE isolates were subjected to short- and long-read whole genome sequencing to perform a detailed genomic characterization of the isolates and of the mobile genetic elements harboring the enzymes. From a total of 1,335 CRE isolates, we observed an increase in the prevalence of CP-CRE, from 11% in 2019 to 38% in 2022. A total of 11 dual CP-CRE isolates were recovered, all of them harboring
bla
KPC
and
bla
NDM
. Species corresponded to
Escherichia coli
(
n
= 6),
Klebsiella pneumoniae
(
n
= 2),
Klebsiella oxytoca
(
n
= 2), and
Citrobacter freundii
(
n
= 1). Dual CP-CRE isolates exhibited resistance to all tested β-lactams except for cefiderocol. The
bla
KPC
and
bla
NDM
encoding genes were located on independent plasmids. Platforms harboring
bla
KPC
were diverse and included IncN, IncF, and IncFIB plasmids. In contrast,
bla
NDM-7
was only found on fairly conserved IncX3 plasmids. We report that a rapid increase of CP-CRE in Chile, alongside with the emergence of multiple bacterial species of CP-CRE co-harboring
bla
KPC-2/3
and
bla
NDM-7
, underscores a critical public health challenge. Our data suggest that the dissemination of
bla
NDM-7
was predominantly facilitated by IncX3 plasmids, whereas the spread of
bla
KPC
involved multiple plasmid backbones. Active surveillance and genomic monitoring are critical to inform public policy and curtail the spread of these highly resistant pathogens.
