Objectives: E. cloacae is an opportunistic organism that causes serious infections, particularly in immuno-compromised and hospitalized patients, along with the emergence of resistance traits. The COVID-19 pandemic has impacted the epidemiological pattern and resistance traits of E. cloacae infections as well as those of other bacteria. The study aims to assess the epidemiological patterns, resistance characteristics and clinical outcomes of E. cloacae in Saudi Arabia and the impact of the COVID-19 pandemic. Methods: King Fahad Medical City in Riyadh provided the data between January 2019 and December 2021 for the retrospective study of 638 isolates of E. cloacae. The clinical outcome of an E. cloacae infection was also determined by collecting and statistically analyzing the clinical records of 153 ICU patients. Results: The total percentage of resistant E. cloacae isolates decreased from 48.36% in 2019 to 38% in 2020 and 37.6% in 2021. The overall mortality rate among ICU patients was 40.5%, with an adult age group having a substantial relative risk value of 1.37. Conclusion: E. cloacae is a prevalent nosocomial infection in which adult age is a significant risk factor for mortality. Moreover, this study emphasizes the importance of comparing E. cloacae resistance trends before and throughout the pandemic period in order to better understand the bacteria’s behaviour.