<jats:p>Colistin is a last-resort antibiotic used in the treatment of multidrug resistant Gram-negative bacteria. However, the activity and efficacy of colistin has been compromised by the worldwide spread of the mobile colistin resistance genes (<jats:italic>mcr-1</jats:italic> to <jats:italic>mcr-10</jats:italic>). In this study, two clinical <jats:italic>Escherichia coli</jats:italic> strains, named <jats:italic>Ec</jats:italic>CAI51, and <jats:italic>Ec</jats:italic>CAI73, harbored <jats:italic>mcr-1</jats:italic>, showed multidrug-resistant phenotypes (with colistin MIC = 4 μg/ml), and belonged to phylogroup D: multilocus sequence type 1011 (ST1011) and phylogroup A: ST744, respectively. Findings revealed the existence of <jats:italic>mcr-1</jats:italic> gene on two conjugable plasmids, pAMS-51-MCR1 (∼122 kb IncP) and pAMS-73-MCR1 (∼33 kb IncX4), in <jats:italic>Ec</jats:italic>CAI51, and <jats:italic>Ec</jats:italic>CAI73, respectively. The <jats:italic>mcr-1</jats:italic>-<jats:italic>pap2</jats:italic> element was detected in the two plasmids. Additionally, the composite transposon (IS<jats:italic>Apl1</jats:italic>-IS<jats:italic>5D</jats:italic>-<jats:italic>pap2</jats:italic>-<jats:italic>mcr-1</jats:italic>-IS<jats:italic>Apl1</jats:italic>) was identified only in pAMS-51-MCR1 suggesting the potential for horizontal gene transfer. The two strains carried from 16 to 18 different multiple acquired antimicrobial resistance genes (ARGs). Additionally, two different multireplicon virulence plasmids (∼117 kb pAMS-51-Vr and ∼226 kb pAMS-73-Vr) carrying the <jats:italic>sit</jats:italic> operon, the Salmochelin siderophore <jats:italic>iroBCDE</jats:italic> operon and other several virulence genes were identified from the two strains. Hierarchical clustering of core genome MLST (HierCC) revealed clustering of <jats:italic>Ec</jats:italic>CAI73, and <jats:italic>Ec</jats:italic>CAI51 with global <jats:italic>E. coli</jats:italic> lineages at HC levels of 50 (HC50) to 100 (HC100) core genome allelic differences. To the best of our knowledge, this study presented the first complete genomic sequences of <jats:italic>mcr-1</jats:italic>-carrying IncP and IncX4 plasmids from human clinical <jats:italic>E. coli</jats:italic> isolates in Egypt. In addition, the study illustrated the <jats:italic>mcr-1</jats:italic> broad dissemination in diverse plasmids and dissimilar <jats:italic>E. coli</jats:italic> clones.</jats:p>