Background: Antibiotic-resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are commonly implicated in health-care associated infections (HAIs). Objectives: The purpose of this study is to assess the antimicrobial susceptibility profile of Gram-negative ESKAPE pathogens, with prime emphasis on the prevalence and risk factors for infections by multidrug-resistant (MDR) strains. Methodology: In this retrospective cohort study, we reviewed the electronic medical and laboratory records of our tertiary health-care facility throughout the period from January 2019 to December 2020. Adult patients identified with infections by any of the Gram-negative ESKAPE bacteria were eligible for our study. The risk factors associated with acquisition of MDR organisms were analyzed using univariate and multivariate models. Results: During the period of interest, a total of 614 Gram-negative ESKAPE isolates were identified, of which 121 were found to be MDR (19.7%). A. baumannii was the leading MDR organism (43.1%), whereas MDR P. aeruginosa was the least common (10.7%). The independent risk factors associated with acquisition of MDR infections included long hospital stays (P < 0.0001), undergoing surgical procedures (P= 0.001), ischemic heart disease (P= 0.005), mechanical ventilation (P= 0.005), and presence of indwelling urinary catheter (P= 0.03). Conclusions: Infections with MDR Gram-negative ESKAPE organisms have an alarming magnitude in our institution. Continued vigilance by the involved health-care workers, stringent compliance to the infection control guidelines, and effective implementation of the antimicrobial stewardship programs are critical measures to decrease the burden of this health problem.