Background: Cirrhosis is a chronic, progressive, and currently incurable disease. Cirrhotic patients often experience uncertainty due to poor control of symptoms and disease recurrence. Although fatigue is a common symptom in patients with liver cirrhosis, this symptom is often ignored by healthcare professionals due to the lack of efficacious treatment options. Improper management of fatigue may trigger greater uncertainty and affect adaptation success. Purpose: To explore the relationship between fatigue and uncertainty and the factors that respectively relate to these two concepts in liver cirrhosis patients. Methods: A cross-sectional, correlational design and convenience sampling were used to recruit 76 liver cirrhotic inpatients from one hospital. Three structured questionnaires, including the Personal Demographic Questionnaire, Brief Fatigue Inventory-Taiwan Form, and Mishel’s Uncertainty in Illness Scale, were used for data collection. Results: (1) The participants suffered from fatigue at a moderate or higher level, with an average score of 5.39 ± 2.34, which affected their daily activities and greatly impacted their recreational activities. Factors that were found to be associated with fatigue included disease severity, albumin level, total bilirubin level, ascites, and the degree to which fatigue affected the performance of daily activities. (2) Uncertainty was found to be at a moderate or higher level, with an average score of 71.81 ± 10.67. Level of fatigue, the degree to which fatigue affected the performance of daily activities, disease severity, and albumin level were found to relate significantly to level of uncertainty. Conclusions/Implications for Practice: Fatigue and uncertainty are prevalent and distressing experiences for patients with liver cirrhosis. A comprehensive assessment and broad-based approach to nursing interventions are necessary in order to alleviate fatigue and uncertainty effectively.