Antimicrobial resistance (AMR) among Gram-negative bacteria (GNB) poses an escalating threat to public health worldwide, including in Saudi Arabia. The country’s healthcare system is under increasing pressure from multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, particularly Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. These pathogens are major culprits in hospital-acquired infections (HAIs), especially in intensive care units (ICUs), where vulnerable patients face the highest risks. This review aims to consolidate current data on the prevalence, resistance patterns, mechanisms of resistance, and key contributing factors associated with GNB in Saudi hospitals. It also explores strategic directions for improving clinical management and public health interventions. We conducted a comprehensive review of peer-reviewed literature published sourcing information from PubMed, Google Scholar, and official Saudi health databases. The data were categorized by bacterial species, geographic region, infection type, and resistance profiles. Findings highlight alarmingly high resistance rates to commonly used antibiotics such as carbapenems, aminoglycosides, fluoroquinolones, and third-generation cephalosporins. The problem is particularly severe with A. baumannii and P. aeruginosa. Additionally, the spread of extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae further limits treatment options. Frequently identified resistance genes include blaKPC, blaNDM, and blaOXA-48. Contributing factors range from the overuse and misuse of antibiotics to gaps in antimicrobial stewardship programs. Unique regional factors, such as the influx of international pilgrims during Hajj, add further complexity. Resistance levels also vary by region, with central and western areas reporting the highest rates. Addressing AMR in Saudi Arabia calls for a coordinated, multi-pronged approach. This includes enhancing nationwide surveillance, reinforcing antimicrobial stewardship, adopting rapid diagnostic tools, and tightening infection control measures. Future efforts should also explore alternative therapies, such as bacteriophage treatments and novel antibiotic combinations. Tackling this public health crisis will require sustained collaboration at both the national and global levels to ensure better clinical outcomes and safeguard public health.
