Introduction: Carbapenem-resistant Enterobacterales (CRE) are particularly worrisome pathogens because of their resistance to last-resort antibiotics, significant morbidity, and mortality. With limited treatment options, new therapeutic choices have become available for the management of CRE infections. Data regarding the efficacy of these novel agents are still limited particularly in a low-middle-income country like Egypt. This study aims to assess the prevalence of different carbapenemase genes among CRE isolates and the susceptibility of these isolates to novel antibiotics for improving antibiotic policy and infection control strategies in Egypt. Methodology: In this cross-sectional study, 260 Enterobacterales were recovered from patients admitted to intensive care units between January and June 2021. Susceptibility testing was conducted using Kirby-Bauer method. Molecular detection of five carbapenemase genes, namely blaKPC, blaIMP, blaVIM, blaNDM, blaOXA-48 was done using polymerase chain reaction (PCR). Results: Of the 260 Enterobacterales, 34.6% were found to be carbapenems resistant. All of the CRE isolates were multi-drug resistant exhibiting resistance to most antibiotics. All isolates harbored one or more carbapenemases genes. The most prevalent was blaNDM (84.4%), followed by blaOXA-48 (73.3%), blaKPC (13.3%), blaIMP (2.2%), while blaVIM gene wasn’t detected. Among 62.2% of the CRE isolates, two or more carbapenemase genes co-existed. For the new antibiotics tested, 100% of CRE resisted ceftolozane/tazobactam, 86.7% resisted ceftazidime/avibactam, 51.1% were resistant to eravacyclin, and 42.2% were resistant to cefiderocol. Conclusions: A high percentage of resistance to carbapenems among Enterobacterales isolates was revealed. blaNDM was found to be the most predominant carbapenemase gene. A high rate of CRE resistance to novel agents signifies a major threat.