Escherichia coli (E. coli) is a major causative organism of complicated urinary tract infections, bloodstream infections, and pneumonia. With the widespread use of antimicrobial agents, the prevalence of carbapenem resistance in E. coli has been increasing with limited therapeutic options. Fluoroquinolone remains a choice in carbapenem-resistant E. coli (CREc) that were once susceptible to the drug. Despite robust studies on the fluoroquinolone-resistant mechanisms of E. coli, few studies focused specifically on the group of CREc. In this study, we used comparative genomics to identify the fluoroquinolone-resistant mechanisms of CREc and detected gyrA D87N mutation in all the fluoroquinolone-resistant and CREc. Moreover, to investigate the mechanism underlying non-carbapenemase-producing carbapenem-resistant E. coli, we targeted the complete genome sequences for in-depth analysis and found a deletion in OmpF (DEL264-269) that might contribute to carbapenem resistance, which has not been reported before. Further studies focusing on the impact of these mutations on the expression levels are warranted. We further investigate the MLST, serotype, fimH type, phylogroup, and clinical characteristics of the CREc. Combination analysis of clinical and genomic characteristics suggests the polyclonal and highly diverse nature of the CREc in Taiwan. This study provides an insight into the molecular epidemiology of CREc in Taiwan.