Background: Ventilator-associated pneumonia (VAP) is a prevalent cause of morbidity and mortality in intensive care units (ICUs). Defined as a nosocomial pneumonia that occurs more than 48 hours after mechanical ventilation initiation, VAP poses significant clinical challenges. While awareness of evidence-based practices is crucial, a gap often exists between knowledge and actual practice among nursing staff. Enhanced adherence to VAP prevention protocols has been linked to reduced incidence rates. Purpose: This study aims to assess the level of nurses’ knowledge and compliance regarding the prevention of VAP in the intensive care unit of King Fahad General Hospital in Saudi Arabia. Method: A descriptive research design was employed, involving 120 ICU nurses selected through convenience non-probability sampling. Result: A total of 96 participants were recruited in this study. The level of knowledge about VAP prevention among ICU nurses was almost good as there were about 57.3% (n=55) of the nurse participants had a good and adequate information. There was significant statistical difference in the mean knowledge score based on the academic qualification but, there was no statistical difference in mean of compliance based on academic qualification. Conclusion: Insufficient nursing knowledge and compliance about VAP assessment and prevention is a serious safety concern in all healthcare settings. The study highlighted that ICU nurses showed (good) moderate knowledge towards VAP prevention.