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The global dissemination of multidrug-resistant Escherichia coli lineages belonging to high- risk clones poses a significant public health threat. Herein we report the identification and genomic profiling of two multidrug-resistant E. coli strains [BL-II-03(2) and BL-II-11(3)] belonging to the O15:H1-D-ST393 (clonal complex 31) worldwide spread clone, isolated from fecal samples of indigenous peoples belonging to two different ethnic groups of remote communities of Brazilian Amazon. Genomic analysis revealed genes and mutations conferring resistance to β-lactams bla TEM-1 , aminoglycosides aadA5 , aph(3″)-Ib , aph(6)-Id , tetracyclines tetB , sulfamethoxazole/trimethoprim sul1 , sul2 , dfrA17 , and fluoroquinolones gyrA (D87N, S83L), parC (S80I, S57T), parE (L416F)]; and presence of IncQ1, IncFIA, and IncFIB(pB171) plasmids. On the other hand, phylogenomics of globally reported E. coli ST393 assigned E. coli strains BL-II-03(2) and BL-II-11(3) to a cluster comprising human isolates from Australia, Canada, China, Sweden, and United States of America. These results might provide valuable information for understanding dissemination of intercontinental multidrug-resistant clones in remote communities with low levels of antibiotic exposure. • Occurrence of MDR Enterobacterales in remote communities of Amazon was investigated. • Fluoroquinolone-resistant E. coli were identified in fecal samples of indigenous peoples. • Genomic data revealed the presence of the international high-risk clone O15:H1-D-ST393. • Wide resistome and gyrA , parC and parE mutations were responsible for MDR phenotype. • Emergence of international MDR E. coli clones in remote communities is discussed. [ABSTRACT FROM AUTHOR]