Escherichia coli sequence type 648 (ST648), a lineage within the clinically important phylogroup F, has disseminated worldwide in humans and animals. In this study, we performed whole-genome sequencing and comparative genomic analysis for two New Delhi metallo-beta-lactamase (bla_NDM-5) carrying E. coli strains: ECsOL198, recovered from a wild Eurasian otter in Northern Lebanon, and ECOL247, isolated from a hospitalized leukemia patient. Both isolates belonged to phylogroup F and serotype O9:H4, and exhibited IncFIA, IncFIB, and IncFII plasmids. They shared a similar antimicrobial resistance profile, including a carbapenemase gene (bla_NDM-5), β-lactamase genes (bla_TEM-1, bla_CTX-M-15, and bla_OXA-1), and other genes that confer resistance to aminoglycosides (acc(3)-Ile, aadA2), sulfonamides (sul1), tetracyclines (tet(A)), and fluoroquinolones (mutations in gyrA and parC). Both isolates also carried common virulence-associated genes related to adhesion, iron acquisition, environmental persistence, and immune evasion. Whole-genome multilocus sequence typing (wgMLST) revealed that both isolates formed a distinct subclade closely related to a bloodstream-derived ST648 isolate from India, indicating limited relatedness to global clones. These findings highlight the transmission of nearly clonal multidrug-resistant E. coli ST648 in both clinical and non-clinical settings, raising concerns about the threat to public health.