Nurses, as primary healthcare providers who maintain regular patient contact, play a crucial role in preventing venous thromboembolism (VTE). This study aims to explore nurses' perceptions, knowledge, and barriers related to VTE prevention. A descriptive cross-sectional study was conducted among 263 staff nurses in governmental hospitals in the Hail region, Kingdom of Saudi Arabia. Data collection took place between January and May 2022. The majority of nurses considered VTE prevention to be an important issue (mean = 4.03±0.614) and perceived the current use of anticoagulant strategies as effective (mean = 2.91±1.16). However, nurses expressed some uncertainty regarding the safety of the current anticoagulant use (mean = 3.79±0.822) and felt that they underutilized available anticoagulant strategies (mean = 2.69±1.01). Generally, nurses demonstrated a good level of knowledge about VTE (83.2%). Gender was found to significantly influence knowledge (t = -2.841; p < 0.005), perception (t = -7.919; p < 0.000; mean = 3.85±0.707), and barriers (t = -4.661; p < 0.000). Regarding age, significant differences were observed in knowledge (F = 5.665; p < 0.004; mean = 15.87±4.39) and perception (F = 13.401; p < 0.000; mean = 4.16±0.782). No significant differences were found in educational attainment, work experience, and position concerning knowledge, perception, and barriers. The working area was found to have a significant impact on knowledge (F = 4.657; p < 0.000), perception (F = 4.347; p < 0.001), and barriers (F = 4.257; p < 0.001). By providing comprehensive and consistent patient education, nurses can play a critical role in minimizing morbidity and mortality rates associated with VTE, making VTE prevention a vital aspect of their responsibilities.