Background: Work-related fatigue is a common health problem among nurses which can affect their performance and decision making. Significance and Aim: The study explores the levels of fatigue and its associated factors among emergency department (ED) nurses in Saudi Arabia. Methods: The study was developed through a cross-sectional quantitative study design. This included the collection of primary quantitative data with a questionnaire prepared and published on REDCap. The study questionnaire was adapted from two tools, namely the OFER 15 and the Copenhagen II tools, respectively. Results: The study established that the Saudi Arabian ED nurses have high acute fatigue (OFER 15 score = 81.11), moderate-high chronic fatigue (OFER 15 score = 74.17), and a high inter-shift recovery index (OFER 15 score = 78.01). In terms of the predictor factors, the study established that for the demographic factors, gender has an impact on chronic and acute fatigue, while work experience impacted acute fatigue and the number of dependents impacted on inter-shift recovery index. On the psycho-social factors, chronic fatigue is influenced by emotional demand (which is a variable used to evaluate the levels to which the nurse is invested, gaining education/skills thus increases job satisfaction) (−0.289), influence at work (−0.310), commitment at the workplace (0.376), rewards (−0.187), stress (0.420), and burnout (0.293), respectively. Acute fatigue is influenced by the emotional demands (0.336), role clarity (−0.128), and the nurses’ well-being and health (−0.034). Finally, the inter-shift recovery index is influenced by the ED nurses’ burnout levels (−0.877). Conclusions: The study indicates a high level of nursing fatigue among the Saudi Arabian ED nurses.