Purpose : This study aimed to elucidate the mediating effect of fatigue on the relationship between pain and quality of life in patients with cancer, thereby providing important insights into symptom management for these patients. Methods : A total of 44 participants (34 females, mean age 57.30 ± 7.66 years) diagnosed with cancer voluntarily participated in this study, which was conducted at a cancer rehabilitation center. The Breakthrough Pain Assessment Tool, Brief Fatigue Inventory, and European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 were used to measure cancer-related pain, fatigue, and quality of life. Mediation analysis was conducted using Hayes' PROCESS macro 3.5 (model 4). Results : Cancer-related pain significantly and positively influenced fatigue (β = 1.085, p < 0.001) and quality of life (β = 0.762, p = 0.001). However, when both pain and fatigue were included in the model, the direct effect of pain on quality of life was not significant (β = 0.137, p = 0.452), while fatigue significantly influenced quality of life (β = 0.576, p < 0.001). Bootstrapping results indicated that the 95% confidence interval for the direct effect of pain on quality of life included zero [-0.226, 0.499], indicating statistical non-significance. Conversely, the confidence interval for the indirect effect of pain on the quality of life through fatigue did not include zero [0.325, 1.007], confirming statistical significance. These findings indicate that fatigue fully mediates the relationship between cancer-related pain and quality of life in patients with cancer. Conclusion : Implementing strategies that simultaneously assess and manage pain and fatigue may contribute to overall improvement in the quality of life of patients with cancer. This study highlights the importance of understanding the interplay between pain and fatigue and advocating an integrated management approach in clinical settings.