Purpose Multidrug-resistant organisms (MDROs) among Gram-negative bacteria (GNB) are a major public health concern worldwide, which can even lead to death. This study was conducted to determine the prevalence of MDROs among isolated GNB in the Security Forces Hospital Dammam (SFHD) and identify its associated risk factors. Materials and Methods A cross-sectional study was performed on the most commonly isolated GNB in SFHD, Acinetobacter spp., Enterobacter spp., Escherichia coli ( E. coli ), Klebsiella pneumoniae , Proteus spp., and Pseudomonas aeruginosa , of non-duplicated clinical samples collected from all hospital units throughout the period from January 2017 to December 2018. Data were collected retrospectively from patients’ medical records, and analyses were conducted using the chi-square test and logistic regression models. Results Of the 1508 GNB included in the study, 969 were multidrug-resistant (MDR; 64.3%). The most commonly identified multidrug-resistant GNB (MDR-GNB) were found in female patients (66.4%) and those aged between 20 and 29 years (21.8%). Urine samples had the highest number of isolated GNB (926 of a total of 1508, 61.4%), and E. coli isolates (53.8%) were the most frequently isolated GNB. Enterobacter spp. had the highest rate of multidrug resistance during the 2 years (64 out of 74, 86.5%). Mechanical ventilation for three or more calendar days was a significant direct risk factor for the development of MDR-GNB (odds ratio [OR]: 2.600, 95% confidence interval [CI]: 1.124–6.012, P = 0.025). Conclusion Multidrug resistance is common among GNBs in SFHD. Antimicrobial stewardship programs in hospitals should be supported and implemented. Medical and public awareness of antibiotic use is another significant way to decrease the burden of MDR.