Objectives: Device-associated nosocomial infections (DANIs) have a major impact on patient morbidity and mortality. Our study aimed to determine the distribution rate of DANIs and causative agents and patterns of antibiotic resistance in the trauma-surgical intensive care unit (ICU). Methods: Our study was conducted at Abusalim Trauma Hospital in Tripoli, Libya. All devices associated with nosocomial infections, including central venous catheters (CVC), endotracheal tubes (ETT), Foley’s urinary catheters, chest tubes, nasogastric tubes (NGT), and tracheostomy tubes, were removed aseptically and examined for Gram-negative bacteria (GNB). Results: During a one-year study period, 363 patients were hospitalized; the overall mortality rate was 29%. A total of 79 DANIs were identified, the most common site of infection was ETT (39.2%), followed by urinary catheters (19%), NGTs (18%), tracheostomy tubes (11%), CVCs (10%), and chest tubes (3%). The most frequently isolated organisms were Klebsiella pneumonia, Acinetobacter baumannii, and Pseudomonas aeruginosa (30%, 20%, and 14%, respectively). Extremely high resistance rates were observed among GNB to ampicillin (99%), cefuroxime (95%), amoxicillin-clavulante (92%), and nitrofurantoin (91%). Lower levels of resistance were exhibited to amikacin (38%), imipenem (38%), and colistin (29%). About 39% of the isolates were defined as multi-drug resistant (MDR). Overall, extended spectrum β-lactmase producers were expressed in 39% of isolates mainly among K. pneumonia (88%). A. baumannii isolates exhibited extremely high levels of resistance to all antibiotics except colistin (100% sensitive). In addition, 56.3% of A. baumannii isolates were found to be MDR. P. aeruginosa isolates showed 46%–55% effectiveness to anti-pseudomonas antibiotics. Conclusions: High rates of DANI’s and the emergence of MDR organisms poses a serious threat to patients. There is a need to strengthen infection control within the ICU environment, introduce surveillance systems, and implement evidence-based preventive strategies.